US9492805B2 - Initiated chemical vapor deposition of vinyl polymers for the encapsulation of particles - Google Patents
Initiated chemical vapor deposition of vinyl polymers for the encapsulation of particles Download PDFInfo
- Publication number
- US9492805B2 US9492805B2 US11/589,683 US58968306A US9492805B2 US 9492805 B2 US9492805 B2 US 9492805B2 US 58968306 A US58968306 A US 58968306A US 9492805 B2 US9492805 B2 US 9492805B2
- Authority
- US
- United States
- Prior art keywords
- certain embodiments
- hydrogen
- particle
- group
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active, expires
Links
- 0 *C(=C([H])[H])N([1*])C.*C(=C([H])[H])N([1*])C(C)=O.*C(=C([H])[H])S(C)(=O)=O.*C(=C([H])[H])S(C)=O.*C(C(=O)N([1*])C)=C([H])[H].*C(C(=O)OC)=C([H])[H].*C(C(=O)SC)=C([H])[H].*C(C(C)=O)=C([H])[H].*C(C)=C([H])[H].*C(OC(C)=O)=C([H])[H].*C(OC)=C([H])[H].*C(SC(C)=O)=C([H])[H].*C(SC)=C([H])[H] Chemical compound *C(=C([H])[H])N([1*])C.*C(=C([H])[H])N([1*])C(C)=O.*C(=C([H])[H])S(C)(=O)=O.*C(=C([H])[H])S(C)=O.*C(C(=O)N([1*])C)=C([H])[H].*C(C(=O)OC)=C([H])[H].*C(C(=O)SC)=C([H])[H].*C(C(C)=O)=C([H])[H].*C(C)=C([H])[H].*C(OC(C)=O)=C([H])[H].*C(OC)=C([H])[H].*C(SC(C)=O)=C([H])[H].*C(SC)=C([H])[H] 0.000 description 22
- MBABOKRGFJTBAE-UHFFFAOYSA-N COS(C)(=O)=O Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N CS(C)(=O)=O Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
-
- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
- C23C16/44—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating
- C23C16/4417—Methods specially adapted for coating powder
-
- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
- C23C16/44—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating
- C23C16/448—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating characterised by the method used for generating reactive gas streams, e.g. by evaporation or sublimation of precursor materials
- C23C16/452—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating characterised by the method used for generating reactive gas streams, e.g. by evaporation or sublimation of precursor materials by activating reactive gas streams before their introduction into the reaction chamber, e.g. by ionisation or addition of reactive species
Definitions
- microparticles and nanoparticles are useful in a wide range of applications in biotechnology, pharmaceutics, optics, electronics, aviation, and aerospace.
- the surface properties of the particles play a crucial role in determining the overall function and performance of a particle-based device; in many cases, functional polymers are used to define the final nature of the particle surface. This fact underscores the importance of strategies for optimal encapsulation, functionalization and modification with polymeric materials of the surfaces of microparticles and nanoparticles.
- Stepwise polyelectrolyte assembly on particle surfaces a novel approach to colloid design. Polym. Adv. Technol. 9, 759-767 (1998).]
- plasma enhanced chemical vapor deposition PECVD
- PECVD plasma enhanced chemical vapor deposition
- Using vibration or fluidization to agitate the particles during deposition coatings have been made on drug microcrystals, ceramic nanoparticles and carbon nanotubes.
- George et al. have disclosed particles having an ultrathin, conformational coating, made using atomic layer deposition methods. These coated particles are useful as fillers for electronic packaging applications, for making ceramic or cermet parts, as supported catalysts, as well as other applications. However, these methods are limited to depositing inorganic films. [George et al. U.S. Pat. No. 6,613,383, herein incorporated by reference; George et al. U.S. Pat. No. 6,913,827, herein incorporated by reference; and George et al. United States patent application Publication No. U.S. 2003/0026989, herein incorporated by reference].
- One aspect of the present invention relates to an all-dry encapsulation method that enables well-defined polymers to be applied around particles of sizes down to the nanoscale.
- the methods are modified forms of initiated chemical vapor deposition (iCVD) using a thermally-initiated radical polymerization to create conformal coatings around individual particles while avoiding agglomeration.
- iCVD initiated chemical vapor deposition
- the present invention also enables the coating of particle surfaces with a range of functional groups via direct incorporation of the functionality into the monomers used or indirectly through a subsequent modification of the surface of a coated particle.
- the method produces high quality functional polymer coatings.
- poly(glycidyl methacrylate) has been coated on multiwalled carbon nanotubes and glass microspheres to introduce the oxirane functionality.
- demonstrating surface design by immobilization after encapsulation the oxirane ring of the glycidyl group was reacted with amine-containing molecules and fluorescent markers.
- iCVD may be used to encapsulate fine drug microcrystals (e.g., below 100 ⁇ m in size) with methacrylic acid copolymers (such as poly(methacrylic acid-co-ethyl acrylate) and poly(methacrylic acid-co-ethylene dimethyacrylate)) for the purpose of conferring enteric release properties.
- methacrylic acid copolymers such as poly(methacrylic acid-co-ethyl acrylate) and poly(methacrylic acid-co-ethylene dimethyacrylate)
- the present invention overcomes many of the challenges facing existing particle encapsulation techniques like particle agglomeration, the use of toxic solvents, and poor quality control over the polymer coating, without any liquid phase or excipient required to produce the conformal coating.
- FIG. 1 depicts the encapsulation of multiwalled carbon nanotubes: (a) transmission electron microscopy (TEM) of uncoated carbon nanotubes, 20-50 nm in diameter, 5-20 ⁇ m in length; and (b) TEM of poly(glycidyl methacrylate)-coated (PGMA-coated) carbon nanotubes, showing conformal coating around each individual particle. Thickness of coating is about 25 nm.
- TEM transmission electron microscopy
- FTIR Fourier transform infrared spectroscopy
- FIG. 4 depicts the characterization of coating on microspheres: (a) XPS surveys of uncoated (top) and PGMA-coated (bottom) microspheres where the sodalime composition of the glass is completely replaced by the PGMA composition of the polymer after iCVD; (b) C 1s XPS of coated spheres and the five fitted component peaks as assigned; and (c) 015 ⁇ PS of coated spheres and the three fitted component peaks as assigned. Peak fitting results yield a close match with that of stoichiometric PGMA.
- FIG. 5 depicts the immobilization of hexamethylenediamine: (a) C 1s XPS of amine-functionalized PGMA-coated microspheres. The additional peak is assigned to the carbons adjacent to the amines; and (b) 015 ⁇ PS of amine-functionalized PGMA-coated microspheres. The additional peak is assigned to the ⁇ -hydroxyl group formed as a result of the oxirane ring opening reaction. Peak fitting results indicate a 65% conversion of the oxirane rings to the amine.
- FIG. 6 depicts the immobilization of fluorescein-5-thiosemicarbazide: CLSM of PGMA-coated microspheres after reaction with the amine-containing fluorescent label.
- the fluorescent ring around each particle suggests circumferentially uniform binding around a stable coating. Thickness of the ring suggests binding across the depth of the coating.
- CLSM of uncoated microspheres subjected to the same immobilization protocol gave no fluorescence.
- FIG. 7 depicts a conventional iCVD reactor used for coating flats.
- FIG. 8 depicts an example of a particle coating reactor capable of iCVD polymer encapsulation. Modified from a rotary evaporator, it contains a feedthrough (top left) and a rotovap (bottom right) attachment.
- FIG. 9 depicts one embodiment of the iCVD apparatus.
- FIG. 10 depicts one embodiment of the inventive feedline, showing the preheat zone and the hot filament zone.
- FIG. 11 depicts FTIR spectra of poly(methacrylic acid-co-ethyl acrylate): (a) Eudragit L 100-55, and (b)-(g) CVD copolymers using acid:acrylate feed ratios of (b) 0.007, (c) 0.027, (d) 0.028, (e) 0.033, (f) 0.050, and (g) 0.071.
- FIG. 12 depicts a (a) plot of acid:acrylate FTIR peak area ratio vs. acid:acrylate feed ratio; (b) plot of acid:acrylate FTIR peak area ratio vs. acid FTIR peak position and acrylate FTIR peak position; and (c) plot to determine reactivity ratios of acid and acrylate units using the copolymer equation.
- FIG. 13 depicts the minimum polymer coating vs. drug particle size thickness based on Röhm's Eudragit methacrylic acid copolymer loading recommendations (polymer dry weight per unit drug surface area).
- FIG. 14 depicts graphs showing the disintegration time of polymer coating vs. initial polymer coating thickness under dissolution pH of 1.2 and 6.8 (note time axes have different units).
- FIG. 15 depicts FTIR spectra of uncoated KBr, PGMA-coated KBr, the PGMA coating and conventional PGMA, demonstrating iCVD is able to produce polymers that are well-defined.
- FIG. 16 depicts FTIR spectra of (a) PGMA film synthesized from hot filament CVD, (b) film deposited from low-power plasma enhanced CVD of GMA, and (c) conventionally polymerized PGMA.
- the adsorption peaks at 907, 848, and 760 cm ⁇ 1 are assigned to the characteristic adsorption bands of the epoxide group.
- FIG. 17 depicts OM images of KBr particles before coating (bottom left) and after coating (bottom right), and of a PGMA shell after the KBr core was dissolved away with water (top right).
- FIG. 18 depicts the effect of monomer volatility on deposition rate and molecular weight.
- FIG. 19 depicts FTIR spectra of polyalkyl acrylates comparing iCVD and conventional polymers.
- FIG. 20 depicts the effect of monomer (butyl acrylate) concentration on deposition rate and molecular weight.
- FIG. 21 depicts FTIR analysis of iCVD poly(methacrylic acid-co-ethyl acrylate).
- MAA the broad OH absorption between 2500 and 3500 cm ⁇ 1 increases.
- the MAA C ⁇ O stretch at ⁇ 1700 cm ⁇ 1 increases relative to the EA C ⁇ O stretch at ⁇ 1735 cm ⁇ 1 .
- FIG. 22 depicts copolymer analysis of iCVD poly(methacrylic acid-co-ethyl acrylate).
- FIG. 23 depicts XPS analysis of iCVD poly(methacrylic acid-co-ethylene dimethacrylate). a) C1s is resolved into four distinct peaks, with peak 3 solely from EDMA. b) O1s is resolved into three distinct peaks, with peak 2 from EDMA and peak 3 from MAA. Spectra yields an MAA:EDMA copolymer ratio of 52:48.
- FIG. 24 depicts spectroscopic ellipsometry analysis of iCVD poly(methacrylic acid-co-ethylene dimethacrylate).
- a) At pH 1.2, there is only a slight shift in the ⁇ curve between t 1 min and 18 h soak.
- b) At pH 7.0, there is a significant shift in the ⁇ curve between t 1, 5 and 25 min soak.
- c) The spectra can be used to derive the change in copolymer film thickness between the initial dry film and the final swollen film under various pH buffer soaks.
- the copolymer remains fairly dense with swelling of about 5%, while at near neutral pH and higher, the copolymer shows significant swelling of greater than about 30%.
- FIG. 25 depicts time release profiles of fluorescein.
- FIG. 26 depicts the controlled release of ibuprofen.
- a novel dry polymer encapsulation method for microparticles and nanoparticles is provided.
- the method based on initiated chemical vapor deposition (iCVD), combines a dry chemical vapor deposition environment with a radical polymerization solution chemistry without the liquid phase; by thermally activating a polymerization initiator in the vapor phase, and combining with monomer vapor, a polymerization reaction is induced on the surfaces of the particles when the reactive species are adsorbed.
- iCVD initiated chemical vapor deposition
- microparticles and nanoparticles can be completely encapsulated with a polymer coating by the iCVD without particle agglomeration.
- an acrylate as the encapsulating polymer, it was shown that surface design can be realized either by the introduction of the desired functionality directly into the polymer, or by a subsequent binding of surface active groups to the polymer. In one example, this result was accomplished by immobilizing fluorescent molecules through a ring-opening reaction of pendant glycidyl moieties.
- iCVD Initiated chemical vapor deposition
- iCVD provides a uniform or substantially uniform coating on rough, fibrous, and porous morphologies with high surface areas.
- the iCVD coating process is compatible with a variety of organic and inorganic materials since it does not depend on evenly wetting the substrate surface.
- the iCVD technique eliminates wet-processing steps which can damage some electronic devices and organic membranes through the wetting or the spin-coating process often used to apply solution-based films.
- iCVD i.g., unpaired electrons.
- the film undergoes reactions with components of the ambient atmosphere (such as water, resulting in a large number of hydroxyl groups). Therefore, non-iCVD films are more susceptible to atmospheric ageing, and degradation of their optical, electrical and chemical properties.
- iCVD produces exceptionally clean polymers with stoichiometric compositions, high molecular weights and having no residual solvents, excipients, glidants or plasticizers.
- plasma-based dry methods fully functional linear polymers are not produced because the high-energy plasma environment results in non-selective chemistries which lead to crosslinked networks.
- iCVD is a suitable method for encapsulating pharmaceutical products, especially those that are susceptible to thermal degradation.
- iCVD generally takes place in a reactor. Traditionally, the surface to be coated was placed on a stage in the reactor and gaseous precursor molecules are fed into the reactor; the stage may be the bottom of the reactor and not a separate entity (see, e.g., FIG. 7 ).
- iCVD can alternatively be set up to allow particle agitation using a rotary mechanism to create a rotating particle bed.
- a tumbler reactor being used for PECVD see Yasuda, H. Luminous Chemical Vapor Deposition and Interface Engineering. Marcel Dekker Incorp. 2004, 467-472.
- FIGS. 8-10 show one embodiment of such a iCVD reactor; the reactor comprises of a modified rotary evaporator with two primary components. One component is a feedthrough attachment for directing vapors in and out, for controlling system pressure, and for electrical power to provide resistive heating to initiate polymerization.
- the other is a rotovap attachment that can rotate a flask containing, in one embodiment, up to about 10 g of particles to speeds of up to about 280 rpm. This rotary motion provides mechanical agitation for more uniform coating.
- the flask sits in a temperature-controlled water bath to keep the particles sufficiently cool to enhance vapor adsorption and promote surface polymerization.
- the reactor has a specially designed vapor feed line that consists of a stainless steel tube with an in-line sheathed heater to preheat and maintain the monomer and initiator as vapors.
- the iCVD reactor has automated electronics to control reactor pressure using a downstream butterfly valve and to control reactant flow rates using calibrated mass flow controllers. Any unreacted vapors may be exhausted from the system through a roots blower-dry pump system ( FIG. 9 ).
- the iCVD coating process can take place at a range of pressures from atmospheric pressure to low vacuum.
- a low operating pressure typically in the range of about 10 Pa to about 100 Pa, can provide an ideal environment for the coating extremely fine objects.
- the pressure is less than about 1 torr; in yet other embodiments the pressure is less than about 0.7 torr or less than about 0.4 torr. In other embodiments the pressure is about 1 torr; or about 0.7 torr; or about 0.4 torr.
- the flow rate of the monomer can be adjusted in the iCVD method.
- the monomer flow rate is about 10 sccm. In other embodiments the flow rate is less than about 10 sccm. In certain embodiments the monomer flow rate is about 5 sccm. In other embodiments the flow rate is less than about 5 sccm. In certain embodiments the monomer flow rate is about 3 sccm. In other embodiments the flow rate is less than about 3 sccm. In certain embodiments the monomer flow rate is about 1.5 sccm. In other embodiments the flow rate is less than about 1.5 sccm. In certain embodiments the monomer flow rate is about 0.75 sccm. In other embodiments the flow rate is less than about 0.75 sccm. When more than one monomer is used (i.e. to deposit co-polymers), the flow rate of the additional monomers, in certain embodiments, may be the same as those presented above.
- the flow rate of the initiator can be adjusted in the iCVD method.
- the initiator flow rate is about 10 sccm. In other embodiments the flow rate is less than about 10 sccm. In certain embodiments the initiator flow rate is about 5 sccm. In other embodiments the flow rate is less than about 5 sccm. In certain embodiments the initiator flow rate is about 3 sccm. In other embodiments the flow rate is less than about 3 sccm. In certain embodiments the initiator flow rate is about 1.5 sccm. In other embodiments the flow rate is less than about 1.5 sccm. In certain embodiments the initiator flow rate is about 0.75 sccm. In other embodiments the flow rate is less than about 0.75 sccm.
- the temperature of the filament can be adjusted in the iCVD method. In certain embodiments the temperature of the filament is about 350° C. In certain embodiments the temperature of the filament is about 300° C. In certain embodiments the temperature of the filament is about 250° C. In certain embodiments the temperature of the filament is about 245° C. In certain embodiments the temperature of the filament is about 235° C. In certain embodiments the temperature of the filament is about 225° C. In certain embodiments the temperature of the filament is about 200° C. In certain embodiments the temperature of the filament is about 150° C. In certain embodiments the temperature of the filament is about 100° C.
- the iCVD coating process can take place at a range of temperatures.
- the temperature is ambient temperature.
- the temperature is about 25° C.; in yet other embodiments the temperature is between about 25° C. and 100° C., or between about 0° C. and 25° C.
- said temperature is controlled by a water bath.
- the iCVD coating process can take place at a range of flask rotating speeds.
- said rotating speed is about 50 rpm. In certain embodiments said rotating speed is about 100 rpm. In certain embodiments said rotating speed is about 150 rpm. In certain embodiments said rotating speed is about 200 rpm. In certain embodiments said rotating speed is about 250 rpm. In certain embodiments said rotating speed is about 300 rpm. In certain embodiments said rotating speed is about 350 rpm.
- typical reactor conditions are about 0.4 torr pressure, about 1.5 sccm monomer flow, about 0.2 sccm initiator flow, about 235° C. filament temperature, about 25° C. water temperature and about 150 rpm rotating speed.
- the rate of polymer deposition is about 1 micron/minute. In certain embodiments, the rate of polymer deposition is between about 1 micron/minute and about 50 nm/minute. In certain embodiments, the rate of polymer deposition is between about 10 micron/minute and about 50 nm/minute. In certain embodiments, the rate of polymer deposition is between about 100 micron/minute and about 50 nm/minute. In certain embodiments, the rate of polymer deposition is between about 1 nm/minute and about 50 nm/minute. In certain embodiments, the rate of polymer deposition is between about 10 nm/minute and about 50 nm/minute. In certain embodiments, the rate of polymer deposition is between about 10 nm/minute and about 25 nm/minute.
- the gaseous initiator of the instant invention is selected from the group consisting of compounds of formula I: A-X—B I wherein, independently for each occurrence, A is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; X is —O—O— or —N ⁇ N—; and B is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
- the gaseous initiator of the instant invention is a compound of formula I, wherein A is alkyl. In certain embodiments, the gaseous initiator of the instant invention is a compound of formula I, wherein R 4 is hydrogen or alkyl. In certain embodiments, the gaseous initiator of the instant invention is a compound of formula I, wherein A is hydrogen. In certain embodiments, the gaseous initiator of the instant invention is a compound of formula I, wherein B is alkyl. In certain embodiments, the gaseous initiator of the instant invention is a compound of formula I, wherein X is —O—O—.
- the gaseous initiator of the instant invention is a compound of formula I, wherein X is —N ⁇ N—. In certain embodiments, the gaseous initiator of the instant invention is a compound of formula I, wherein A is —C(CH 3 ) 3 ; and B is —C(CH 3 ) 3 . In certain embodiments, the gaseous initiator of the instant invention is a compound of formula I, wherein A is —C(CH 3 ) 3 ; X is —O—O—; and B is —C(CH 3 ) 3 .
- the gaseous initiator is selected from the group consisting of hydrogen peroxide, alkyl or aryl peroxides (e.g., tert-butyl peroxide), hydroperoxides, halogens and nonoxidizing initiators, such as azo compounds (e.g., bis(1,1-dimethyl)diazene).
- gaseous initiator encompasses initiators which may be liquids or solids at STP, but upon heading may be vaporized and fed into the chemical vapor deposition reactor.
- One aspect of this invention relates to coated particles and methods of coating them.
- coatings are provided onto the surfaces of various particulate materials.
- the size of the particles will depend somewhat on the particular material and the particular application.
- suitable particle sizes the nanometer range (e.g., about 0.001 ⁇ m to about 500 ⁇ m).
- particle sizes range from about 0.005 ⁇ m to about 501 ⁇ m, or from about 0.1 ⁇ m to 10 ⁇ m, or from about 0.4 ⁇ m to about 10 ⁇ m.
- Particle size can also be expressed in terms of the surface area of the particles.
- particulate materials have surface areas in the range of about 0.1 m 2 /g to 200 m 2 /g.
- particulate materials can be coated, with the composition of the uncoated particle and that of the coating typically being selected together so that the surface characteristics of the particle are modified in a way that is desirable for a particular application.
- porate materials include, for example, biologically active substances (see below), ceramics and glasses, such as fused silica, fumed silica, or soda glass; oxides such as silica, alumina, zirconia, ceria, yttria, and titania, as well as oxides of tin, indium and zinc and their doped forms (e.g., boron); carbides, such as tantalum carbide (TaC), boron carbide (B 4 C), silicon carbide (SiC), tantalum carbide (TaC), boron carbide (B 4 C), silicon carbide (SiC), titanium carbide (TiC); nitrides, such as titanium nitride (TiN) and boron nitride (B 4 N); metals, such as gold (Au), silicon (Si), silver (Ag), platinum (Pi) and nickel (Ni); minerals, such as calcium fluoride (CaF 2 )
- Nanocrystalline Materials include ceramics, metals, and metal oxide nanoparticles.
- ceramics, metals, and metal oxide nanoparticles are assembled from nanometer-sized building blocks, mostly crystallites.
- the building blocks may differ in their atomic structure, crystallographic orientation, or chemical composition.
- incoherent or coherent interfaces may be formed between them, depending on the atomic structure, the crystallographic orientation, and the chemical composition of adjacent crystallites.
- materials assembled of nanometer-sized building blocks are microstructurally heterogeneous, consisting of the building blocks (e.g., crystallites) and the regions between adjacent building blocks (e.g., grain boundaries).
- Carbon Nanotubes are hollow cylinders of carbon atoms. Their appearance is that of rolled tubes of graphite such that their walls are hexagonal carbon rings and are often formed in large bundles. The ends of CNTs are domed structures of six-membered rings capped by a five-membered ring.
- CNTs single-walled carbon nanotubes
- MWNTs multi-walled carbon nanotubes
- Dendrimers (Organic Nanoparticles).
- these nanometer sized, polymeric systems are hyperbranched materials having compact hydrodynamic volumes in solution and high, surface, functional group content. They may be water-soluble but, because of their compact dimensions, they do not have the usual rheological thickening properties that many polymers have in solution.
- Dendrimers the most regular members of the class, are synthesized by step-wise convergent or divergent methods to give distinct stages or generations. Dendrimers are defined by their three components: a central core, an interior dendritic structure (the branches), and an exterior surface (the end groups).
- Hybrid inorganic-organic composites are an emerging class of new materials that hold significant promise. Materials are being designed with the good physical properties of ceramics and the excellent choice of functional group chemical reactivity associated with organic chemistry. New silicon-containing organic polymers, in general, and polysilsesquioxanes, in particular, have generated a great deal of interest because of their potential replacement for and compatibility with currently employed, silicon-based inorganics in the electronics, photonics, and other materials technologies. Hydrolytic condensation of trifunctional silanes yields network polymers or polyhedral clusters having the generic formula (RSiO 1.5 ) n .
- silsesquioxanes They are known as silsesquioxanes. Each silicon atom is bound to an average of one and a half (sesqui) oxygen atoms and to one hydrocarbon group (ane). Typical functional groups that may be hydrolyzed/condensed include alkoxy- or chlorosilanes, silanols, and silanolates.
- the particulate is preferably non-agglomerated after the polymer is deposited.
- “Non-agglomerated” means that the particles do not form significant amounts of agglomerates during the process of coating the substrate particles with the inorganic material. Particles are considered to be non-agglomerated if (a) the average particle size does not increase more than about 5%, not more than about 2%, or not more than about 1% (apart from particle size increases attributable to the coating itself) as a result of depositing the coating, or (b) if no more than 2 weight %, or no more than 1 weight % of the particles become agglomerated during the process of depositing the polymeric material.
- the ability to deposit the polymers without forming agglomerates is important. Gas transport mechanisms allow the reactants to diffuse to the surfaces of individual particles that are in contact so that individual particle surfaces can be coated, even if those particle surfaces are in contact with surfaces of other particles. This process is aided by particle agitation using a rotary mechanism, as described herein.
- the particles of the invention have an ultrathin coating.
- ultrathin it is meant that the average thickness of the coating is, between about 0.001 nm and about 100 nm. In certain embodiments the average thickness of the coating is between about 0.001 nm and 50 nm. In certain embodiments, the average thickness of the coating is between about 0.001 nm and about 1 nm. In certain embodiments, the average thickness of the coating is from about 0.1 nm to about 50 nm; or from about 0.5 nm to about 35 nm; or from about 1 nm and about 10 nm. In certain embodiments, the ultrathin coating is conformal.
- the thickness of the coating is relatively uniform across the surface of the particle, so that the surface shape of the coated particle closely resembles that of the uncoated particle.
- the ultrathin coating smoothes out deformities in the underlying particle.
- the composition of the coating can vary considerably depending on the composition of the underlying particle and the intended end-use of the coated particle.
- the coating may perform a variety of functions, depending on the nature of the base particle and the intended application. Thus, one function of the coating may be to modify the surface properties of the base particle. Another possible function of the coating involves the case where a base particle has a surface that behaves in some undesirable way in a particular environment. Alternately, the coating may itself be a reagent or catalyst in some chemical reaction. In these cases, this invention provides a convenient method of providing a high surface area reactive or catalytic material, and/or provides a way for finely dispersing the coating material.
- the polymer or co-polymer comprises one or more recurring monomeric units selected from the group consisting of
- R is selected from the group consisting of hydrogen and alkyl
- R 1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl
- X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH 2 ) n Y
- Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10
- the polymer or co-polymer comprises one or more recurring monomeric units selected from the group consisting of poly(glycidyl methacrylate), p-bromophenyl methacrylate, pentabromophenyl methacrylate, n-vinyl carbazole, p-divinyl benzene, styrene, alpha methyl styrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2,3-dichlorostyrene, 2,4-dichlorostyrene, 2,5-dichlorostyrene, 2,6-dichlorostyrene, 3,4-dichlorostyrene, 3,5-dichlorostyrene, 2-bromostyrene, 3-bromostyrene, 4-bromostyrene, 2,3-dibromostyrene, 2,4-dibromostyrene, 2,5-dibromostyrene, 2,6-d
- inventive polymer or co-polymer coatings are crosslinked.
- a suitable crosslinker is, for example, a low molecular weight di- or polyvinylic crosslinking agent such as ethyleneglycol diacrylate or dimethacrylate, di-, tri- or tetraethylen-glycol diacrylate or dimethacrylate, allyl (meth)acrylate, a C 2 -C 8 -alkylene diacrylate or dimethacrylate, divinyl ether, divinyl sulfone, di- and trivinylbenzene, trimethylolpropane triacrylate or trimethacrylate, pentaerythritol tetraacrylate or tetramethacrylate, bisphenol diacrylate or dimethacrylate, methylene bisacrylamide or methylene bismethacrylamide, ethylene bisacrylamide or ethylene bismethacrylate, ethylene bisacrylamide or ethylene bismethacrylate,
- FIG. 15 shows the FTIR spectra comparing the PGMA coating on the KBr to conventional PGMA, demonstrating that iCVD produces polymers that are spectroscopically identical to those prepared through solution phase synthesis routes.
- FIG. 16 b which depicts the PECVD GMA, demonstrates the superiority of the iCVD technique, as evidenced by the extent of decomposition present in the PECVD film.
- FIG. 17 shows OM images of the KBr particles before and after coating, demonstrating no agglomeration.
- FIG. 17 also shows clearly an image of the PGMA shell after dissolution of the KBr core.
- argon As the diluent to alter the partial pressure of the monomer while keeping the total pressure and flowrates constant.
- P i /P sat ratios there is a second order dependence of deposition rate on surface monomer concentration, while at higher P i /P sat ratios, the dependence becomes linear (see FIG. 20 for plot).
- molecular weight only showed a linear increase with surface monomer concentration.
- FIG. 1 shows that particles down to the nanoscale, such as carbon nanotubes, can be individually encapsulated with a polymer.
- a polymer Using glycidyl methacrylate as the monomer and tert-amyl peroxide as the initiator, both conventional reactants in polymerization chemistries, poly(glycidyl methacrylate) (PGMA) can be formed on the surface of the particles by thermally activating the initiator in the gas phase through an array of electrically heated wires at a temperature of about 250° C. to about 300° C. and promoting surface adsorption of activated species and the monomer vapor on the particles through contact with a cooled stage at a temperature between about 20° C. to about 30° C. Shown in FIG.
- iCVD multiwalled carbon nanotubes (about 20 nm to about 50 nm in diameter, about 5 ⁇ m to about 20 ⁇ m in length) prior to iCVD coating.
- the PGMA coating is seen under transmission electron microscopy (TEM) to encapsulate each nanotube, with a coating thickness on the order of 25 nm.
- TEM transmission electron microscopy
- iCVD is able to handle asymmetric particles with high aspect ratios, which for these nanotubes are between about 1,000 to about 10,000 in length-to-diameter.
- iCVD provides a useful way to surface functionalize nanotubes in a non-covalent fashion without destroying the sp 2 nature of the nanotubes, which will help preserve their properties, such as electrical conductivity and tensile stiffness.
- Microspheres are an important area of particle technology and engineering. Microspheres that incorporate peptides and proteins are now being used as extended-release agents in drug delivery. [Okada, H. One- and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate. Adv. Drug Deliv. Rev. 28, 43-70 (1997); and Cleland, J. L., Johnson, O. L., Putney, S. & Jones, A. J. S. Recombinant human growth hormone poly(lactic-co-glycolic acid) microsphere formulation development.
- FIG. 3 shows glass microspheres viewed under scanning electron microscopy (SEM) which have undergone iCVD encapsulation with PGMA, this time using a rotating bed to physically agitate the particles.
- SEM scanning electron microscopy
- the glass microspheres remain unagglomerated after the coating process when comparing FIG. 3 a with FIG. 3 c .
- These microspheres which have an average diameter of 28.5 ⁇ m are much smaller than the 100 ⁇ m limit below which liquid spray coating will usually cause significant particle agglomeration.
- the thinness of the coating makes it visually hard to discern through SEM, a similar comparison at a higher magnification between FIGS. 3 b and 3 d shows that the PGMA coating appears to have reduced the grainy surface morphology inherent in the uncoated microspheres.
- iCVD Unlike methods that adsorb polymers onto particle surfaces, iCVD allows the polymer to form directly at the particle surface making it more likely to obtain a more conformal and smoother encapsulating shell than would be possible with layering a pre-formed polymer that often requires glidants, plasticizers and heat to enable the polymer to flow and amalgamate into a continuous coating.
- the composition of the PGMA coating on the glass microspheres was analyzed using X-ray photoelectron spectroscopy (XPS) as depicted in FIG. 4 .
- XPS X-ray photoelectron spectroscopy
- FIG. 4 a Survey spectra before and after iCVD reveal the loss of peaks associated with the soda-lime composition of the pristine microspheres and the appearance of the peaks related to the PGMA polymer, indicating that the microspheres are completely covered by the polymer.
- the resulting coating agrees well with the expected stoichiometry for PGMA.
- There are five distinct carbon environments for PGMA which are resolvable by XPS.
- iCVD is thus able to produce extremely well-defined polymer compositions necessary for precise surface engineering. By choosing the appropriate iCVD polymerization chemistry, specific functional groups can be incorporated onto the particle surface simply through the functionality of the polymer encapsulating layer.
- SURFACE IMMOBILIZATION ON MICROPARTICLES surface design can be tailored by subsequently binding desired functional groups onto the polymer coating.
- PGMA as the polymer shell
- the presence of the oxirane ring affords the binding of target molecules through a ring-opening reaction.
- the oxirane ring is susceptible to nucleophilic attack by a primary amine, sulfhydryl or hydroxyl group to form a secondary amine, thioether or ether bond, respectively, together with a ⁇ -hydroxyl group from the opened ring.
- FIG. 5 shows the XPS results after soaking PGMA-coated glass microspheres in a 0.5 M hexamethylenediamine solution in ethanol at 60° C. for 5 h. Both the C 1s and O 1s spectra reveal new bonding environments, attributed to carbons adjacent to the amines and to oxygen of the ⁇ -hydroxyl groups (see FIG. 5 for assignments), demonstrating that binding has occurred although there is still a presence of the oxirane ring. Peak fitting calculations indicate that 65% of the glycidyl groups have been converted to the amine. This post-encapsulation immobilization step provides another way to design particle surfaces with the desired functionality or active site.
- fluorescent markers can be immobilized onto PGMA-coated microspheres simply by coupling an amine-containing fluorescent molecule, such as fluorescein-5-thiosemicarbazide (FTSC), to the oxirane ring of the glycidyl group.
- FTSC fluorescein-5-thiosemicarbazide
- FIG. 6 shows CLSM images of PGMA-encapsulated microspheres which have been treated with a FTSC solution in pH 8.0 phosphate buffer at 60° C. for 5 h.
- the fluorescently green ring around each particle confirms that binding of the fluorescent marker to the PGMA is achieved.
- the particles to be coated can be biologically active substances.
- the biologically active substance of the invention can vary widely with the purpose for the composition.
- the active substance(s) may be described as a single entity or a combination of entities.
- the delivery system is designed to be used with biologically active substances having high water-solubility as well as with those having low water-solubility to produce a delivery system that has controlled release rates.
- biologically active substance includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
- Non-limiting examples of broad categories of useful biologically active substances include the following therapeutic categories: anabolic agents, antacids, anti-asthmatic agents, anti-cholesterolemic and anti-lipid agents, anti-coagulants, anti-convulsants, anti-diarrheals, anti-emetics, anti-infective agents, anti-inflammatory agents, anti-manic agents, anti-nauseants, anti-neoplastic agents, anti-obesity agents, anti-pyretic and analgesic agents, anti-spasmodic agents, anti-thrombotic agents, anti-uricemic agents, anti-anginal agents, antihistamines, anti-tussives, appetite suppressants, biologicals, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange resins, laxative
- Encapsulation of drugs with synthetic polymers is one effective means to introduce temporal or target control over drug delivery.
- the polymer shell may act as a diffusion membrane for a timed release of the drug from the core or as a protective barrier that disintegrates in a specific region within the body for a targeted release.
- the polymer coating may also act to mask any undesirable taste of orally dispensed drugs. Further, the polymer coating may act as a protective layer from moisture to prolong the shelf life of the drug.
- the primary goal is to target drug release in the intestines without premature drug dissolution in the stomach.
- enteric formulations are currently available and they fall into two main categories based on their general chemical structure, one is based on cellulose derivatives, such as ethyl cellulose, hydroxypropyl cellulose and cellulose acetate phthalate, the other is a class of polyacrylates containing functional groups, such as methacrylic acid copolymers.
- ibuprofen is selected as a model drug compound.
- Ibuprofen is well-known as a non-steroidal, anti-inflammatory drug (NSAID) used to treat painful and inflammatory conditions, such as rheumatoid arthritis, osteroarthritis, ankylosing spondylitis, mild to moderate pain, dysmenorrhoea, vascular headache and fever.
- NSAID non-steroidal, anti-inflammatory drug
- the present invention is directed to methacrylic acid copolymers as enteric coatings around ibuprofen particles, of about 5 ⁇ m to about 35 ⁇ m in diameter, using a initiated chemical vapor deposition (iCVD) process.
- Current coating methods including spray coating and fluidized bed coating from polymer solutions, are limited to coating particles of sizes larger than 100 ⁇ m. The ability to go to smaller particles improves drug absorption, allowing more convenient dosage forms, such as tablets, to be provided to patients.
- the fractions of MAA and EA in the monomer feed were also determined. These necessarily represent monomer fractions at the reaction surface rather than in the vapor phase since copolymerization is expected to occur only at the surface.
- FIG. 22 a plots the change in F A as a function of ⁇ A , revealing a general increase in MAA in the copolymer as more MAA was present in the feed.
- MAA has a much greater tendency to add to its own type of propagating species when copolymerization occurs in the bulk liquid phase than when at the surface. This may be due to the greater ease with which MAA can orient favorably with each other through hydrogen bonding in a fluid phase that would facilitate self-propagation over cross-propagation.
- the product, r A .r B 0.17, suggests that iCVD copolymerization follows a moderate alternating behavior, with each type of propagating radical preferring to add the other monomer.
- FIG. 23 shows high resolution C 1 s and O 1 s XPS spectra of a P(MAA-EDMA) copolymer.
- the spectra have been resolved into four carbon and three oxygen environments, as assigned in FIG. 23 .
- peak 3 in FIG. 23 a belongs only to an EDMA carbon while peaks 2 and 3 in FIG. 23 b belong separately to an EDMA and an MAA oxygen, respectively, it was possible to do a constrained fitting of both spectra simultaneously and thereby calculate an MAA:EDMA copolymer ratio of 52:48.
- the P(MAA-EDMA) copolymer did not swell appreciably ( ⁇ 5%) in acidic conditions, while swelling considerably (>30%) at near neutral and higher pH. There appears to be an abrupt transition at a pH between 5.0 and 6.5. This clearly demonstrates the enteric property of the iCVD P(MAA-EDMA) copolymer.
- the pH-dependent swelling behavior of the P(MAA-EDMA) copolymer was made use of to demonstrate the enteric release of active agents.
- fluorescein was layered on top of silicon as a thin film, which was then encapsulated with the iCVD P(MAA-EDMA) copolymer coating. Release of fluorescein was then traced over time in different pH buffer environments, as shown in FIG. 25 . Without any coating, fluorescein was completely released within 10 min, with a more rapid dissolution at pH 6.8 compared to pH 1.2 ( FIG. 25 a ).
- FIG. 26 a gives the time release profiles, comparing uncoated and coated ibuprofen at pH 1.2 and 7.4. Release under a near neutral environment was relatively fast regardless of whether a coating was present or not while release under an acidic environment showed a significant delay with the added coating, increasing the time for complete dissolution by over 100% ( FIG. 26 b ).
- iCVD is an effective method for producing copolymer thin films and coatings via a free radical polymerization mechanism, with the ability to tune copolymer ratios systematically by simply adjusting comonomer feed ratios.
- iCVD is ideal for encapsulating thermally sensitive drugs.
- iCVD is able to encapsulate fine drug particles below 100 ⁇ m in size with methacrylic acid copolymer coatings and impart enteric release capabilities.
- These iCVD coatings offer a barrier against acid conditions while minimally affecting release under near neutral environments due to their pH-dependent swelling behavior. The iCVD coating treatment would ultimately benefit patients which undergo prolonged therapy with drugs that are prone to cause stomach ulcerations and bleeding.
- compositions and methods of the invention find application in, for example, thermal barriers, optical (visible and UV) barriers, image enhancement, ink-jet materials, coated abrasive slurries, information-recording layers, targets drug delivery, gene therapy, photonics, surface emobilization, as well as multifunctional nanocoatings.
- high surface area is advantageous; high surface areas can be attained either by fabricating small particles or clusters where the surface-to-volume ratio of each particle is high, or by creating materials where the void surface area (pores) is high compared to the amount of bulk support material.
- Materials such as highly dispersed supported metal catalysts and gas phase clusters fall into the former category, and microporous (nanometer-pored) materials such as zeolites, high surface area inorganic oxides, porous carbons, and amorphous silicas fall into the latter category.
- microporous materials for energy storage and separations technologies including nanostructured materials for highly selective adsorption/separation processes such as H 2 O, H 2 S, or CO 2 removal; high capacity, low volume gas storage of H 2 and CH 4 for fuel cell applications and high selectivity; high permeance gas separations such as O 2 enrichment; and H 2 separation and recovery;
- thermal barrier materials for use in high temperature engines (3) understanding certain atmospheric reactions; (4) incorporation into construction industry materials for improved strength or for fault diagnostics; (5) battery or capacitor elements for new or improved operation; (6) biochemical and pharmaceutical separations; or (7) product-specific catalysts for almost every petrochemical process.
- a hydrogel is a colloidal gel in which water is the dispersion medium.
- Hydrogels are superabsorbent (they can contain over 90% of water) natural or synthetic polymers.
- the inventive films function as hydrogels when soaked in water [See Gleason, K. et al. U.S. patent application Ser. No. 11/198,932, hereby incorporated by reference.]
- Nanoscale dispersions and coatings of the type disclosed herein may find uses in areas of ceramics, cosmetics, biosensors, colorants, and abrasion-resistant polymers.
- Other applications include imaging ink jet materials, electrophotography, pharmaceuticals, flavor enhancers, pesticides, lubricants, and other proprietary applications specific to industry.
- Still another application is in a new, post-silicon generation of electronic devices that includes nanotubes and fullerenes as constituent units of carbon nanoelectronic devices; note that here, dispersion takes on a more quantum consideration in which the number of atoms in a cluster is compared to the number of surface atoms to determine its dispersion function.
- nanoscience such as particles and methods of the instant invention, may help control the properties of the inks themselves.
- the production and use of nanoengineered ink products benefits from such complimentary technology as laser-assist delivery of the ink jet droplet to maintain an accurate deposit of the ink on its target.
- Another application in this field is using nanoscale properties to tailor the inks to achieve ideal absorption and drying times for desired color properties and permanency.
- Chemical or physical sensors often use nanoparticles because they provide high surface area for detecting the state of chemical reactions, because the quality of detection signals is improved, and because earlier and more accurate determination of leakage reduces waste.
- Some commercial sensors and actuators composed of thin films are already used for environmental vapor monitoring in reactors, for example.
- polymer means a molecule, formed by the chemical union of two or more oligomer units.
- the chemical units are normally linked together by covalent linkages.
- the two or more combining units in a polymer can be all the same, in which case the polymer is referred to as a homopolymer. They can be also be different and, thus, the polymer will be a combination of the different units.
- These polymers are referred to as copolymers.
- the polymer coating is a block copolymer, random copolymer, graft polymer, or branched copolymer.
- weight average molecular weight refers to a particular measure of the molecular weight of a polymer.
- the weight average molecular weight is calculated as follows: determine the molecular weight of a number of polymer molecules; add the squares of these weights; and then divide by the total weight of the molecules.
- number average molecular weight refers to a particular measure of the molecular weight of a polymer.
- the number average molecular weight is the common average of the molecular weights of the individual polymer molecules. It is determined by measuring the molecular weight of n polymer molecules, summing the weights, and dividing by n.
- polydispersity index refers to the ratio of the “weight average molecular weight” to the “number average molecular weight” for a particular polymer; it reflects the distribution of individual molecular weights in a polymer sample.
- heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
- Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
- alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
- a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chain, C 3 -C 30 for branched chain), and alternatively, about 20 or fewer.
- cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
- lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
- lower alkenyl and “lower alkynyl” have similar chain lengths.
- aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
- alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
- aryl is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
- aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaromatics.”
- the aromatic ring may be substituted at one or more ring positions with such substituents as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, —CF 3 , —CN, or the like.
- aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
- ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively.
- 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
- heterocyclyl refers to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms.
- Heterocycles may also be polycycles.
- Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
- the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF 3 , —CN, or the like.
- substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
- polycyclyl or “polycyclic group” are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings”. Rings that are joined through non-adjacent atoms are termed “bridged” rings.
- Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF 3 , —CN, or the like.
- substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, si
- carrier is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
- nitro is art-recognized and refers to —NO 2 ;
- halogen is art-recognized and refers to —F, —Cl, —Br or —I;
- sulfhydryl is art-recognized and refers to —SH;
- hydroxyl means —OH;
- sulfonyl is art-recognized and refers to —SO 2 ⁇ .
- Halide designates the corresponding anion of the halogens, and “pseudohalide” has the definition set forth on page 560 of “Advanced Inorganic Chemistry” by Cotton and Wilkinson.
- amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
- R50, R51, R52 and R53 each independently represent a hydrogen, an alkyl, an alkenyl, —(CH 2 ) m —R61, or R50 and R51 or R52, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
- R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
- R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or —(CH 2 ) m —R61.
- alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
- acylamino is art-recognized and refers to a moiety that may be represented by the general formula:
- R50 is as defined above
- R54 represents a hydrogen, an alkyl, an alkenyl or —(CH 2 ) m —R61, where m and R61 are as defined above.
- amino is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:
- alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
- the “alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl, —S-alkynyl, and —S—(CH 2 ) m —R61, wherein m and R61 are defined above.
- Representative alkylthio groups include methylthio, ethyl thio, and the like.
- X50 is a bond or represents an oxygen or a sulfur
- R55 and R56 represents a hydrogen, an alkyl, an alkenyl, —(CH 2 ) m —R61 or a pharmaceutically acceptable salt
- R56 represents a hydrogen, an alkyl, an alkenyl or —(CH 2 ) m —R61, where m and R61 are defined above.
- X50 is an oxygen and R55 or R56 is not hydrogen
- the formula represents an “ester”.
- X50 is an oxygen
- R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a “carboxylic acid”.
- X50 is an oxygen, and R56 is hydrogen
- the formula represents a “formate”.
- the oxygen atom of the above formula is replaced by sulfur
- the formula represents a “thiolcarbonyl” group.
- X50 is a sulfur and R55 or R56 is not hydrogen
- the formula represents a “thiolester.”
- X50 is a sulfur and R55 is hydrogen
- the formula represents a “thiolcarboxylic acid.”
- X50 is a sulfur and R56 is hydrogen
- the formula represents a “thiolformate.”
- X50 is a bond, and R55 is not hydrogen
- the above formula represents a “ketone” group.
- X50 is a bond, and R55 is hydrogen
- the above formula represents an “aldehyde” group.
- carbamoyl refers to —O(C ⁇ O)NRR′, where R and R′ are independently H, aliphatic groups, aryl groups or heteroaryl groups.
- oxo refers to a carbonyl oxygen ( ⁇ O).
- oxime and “oxime ether” are art-recognized and refer to moieties that may be represented by the general formula:
- R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or —(CH 2 ) m —R61.
- the moiety is an “oxime” when R is H; and it is an “oxime ether” when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or —(CH 2 ) m —R61.
- alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
- Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
- An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH 2 ) m —R61, where m and R61 are described above.
- R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
- R57 is as defined above.
- sulfamoyl is art-recognized and refers to a moiety that may be represented by the general formula:
- sulfonyl is art-recognized and refers to a moiety that may be represented by the general formula:
- R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
- sulfoxido is art-recognized and refers to a moiety that may be represented by the general formula:
- Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
- each expression e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
- Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively.
- a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.
- substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
- substituted is also contemplated to include all permissible substituents of organic compounds.
- the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
- Illustrative substituents include, for example, those described herein above.
- the permissible substituents may be one or more and the same or different for appropriate organic compounds.
- the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
- One aspect of the present invention relates to a coated particle comprising a particle and a coating of polymerized monomers on the surface of said particle; wherein said particle has an surface area of between about 10 nm 2 and about 30 mm 2 ; said monomer is selected from the group consisting of
- R is selected from the group consisting of hydrogen and alkyl
- R 1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl
- X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH 2 ) n Y
- Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive.
- the present invention relates to the aforementioned particle, wherein R is hydrogen. In certain embodiments, the present invention relates to the aforementioned particle, wherein R is methyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein X is —(CH 2 ) n Y. In certain embodiments, the present invention relates to the aforementioned particle, wherein Y is alkyl, cycloalkyl, heterocycloalkyl, aryl, nitro, halo, hydroxyl, alkyoxy, aryloxy, amino, acylamino, amido, or carbamoyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein n is 3-8 inclusive.
- Another aspect of the present invention relates to a coated particle comprising a particle and a coating of polymerized monomers on the surface of said particle; wherein said particle has a surface area of between about 10 nm 2 microns and about 30 mm 2 ; said monomer is selected from the group consisting of
- R is selected from the group consisting of hydrogen and alkyl;
- R 1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl;
- R 2 is independently selected from the group consisting of hydrogen, alkyl, bromine, chlorine, hydroxyl, alkyoxy, aryloxy, carboxyl, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido;
- X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH 2 ) n Y;
- Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoara
- the present invention relates to the aforementioned particle, wherein R is hydrogen. In certain embodiments, the present invention relates to the aforementioned particle, wherein R is methyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein R 1 is aralkyl or carboxyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein R 2 is independently selected from the group consisting of hydrogen, alkyl, bromine and chlorine. In certain embodiments, the present invention relates to the aforementioned particle, wherein X is hydrogen or —(CH 2 ) n Y.
- the present invention relates to the aforementioned particle, wherein Y is alkyl, cycloalkyl, heterocycloalkyl, aryl, nitro, halo, hydroxyl, alkyoxy, aryloxy, amino, acylamino, amido, or carbamoyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein n is 3-8 inclusive.
- Another aspect of the present invention relates to a coated particle comprising a particle and a coating of polymerized monomers on the surface of said particle; wherein said particle has a surface area of between about 10 nm 2 and about 30 mm 2 microns; said monomer is
- R is selected from the group consisting of hydrogen and methyl;
- R 2 is independently selected from the group consisting of hydrogen, methyl, bromine and chlorine;
- X is hydrogen or —(CH 2 ) n Y;
- Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive.
- the present invention relates to the aforementioned particle, wherein R is hydrogen. In certain embodiments, the present invention relates to the aforementioned particle, wherein R is methyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein R 2 is independently selected from the group consisting of hydrogen and methyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein R 2 is independently selected from the group consisting of hydrogen and bromine. In certain embodiments, the present invention relates to the aforementioned particle, wherein R 2 is independently selected from the group consisting of hydrogen and chlorine. In certain embodiments, the present invention relates to the aforementioned particle, wherein Y is hydrogen or heterocyloalkyl.
- the present invention relates to the aforementioned particle, wherein Y is hydrogen. In certain embodiments, the present invention relates to the aforementioned particle, wherein Y is an oxirane. In certain embodiments, the present invention relates to the aforementioned particle, wherein n is 3-8 inclusive.
- Another aspect of the present invention relates to a coated particle comprising a particle and a coating of polymerized monomers on the surface of said particle; wherein said particle has a surface area of between about 10 nm 2 and about 30 mm 2 ; and said monomer is selected from the group consisting of poly(glycidyl methacrylate), p-bromophenyl methacrylate, pentabromophenyl methacrylate, n-vinyl carbazole, p-divinyl benzene, styrene, alpha methyl styrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2,3-dichlorostyrene, 2,4-dichlorostyrene, 2,5-dichlorostyrene, 2,6-dichlorostyrene, 3,4-dichlorostyrene, 3,5-dichlorostyrene, 2-bromostyrene, 3-bromostyrene, 4-
- the present invention relates to the aforementioned particle, further comprising an additional monomer, to yield a copolymer on said surface.
- the additional monomer may be any monomer as described herein.
- the present invention relates to the aforementioned particle, further comprising a crosslinker, thereby forming a crosslinked polymer coating.
- the crosslinker may be selected from the group consisting of a low molecular weight di- or polyvinylic crosslinking agent such as ethyleneglycol diacrylate or dimethacrylate, di-, tri- or tetraethylen-glycol diacrylate or dimethacrylate, allyl (meth)acrylate, a C 2 -C 8 -alkylene diacrylate or dimethacrylate, divinyl ether, divinyl sulfone, di- and trivinylbenzene, trimethylolpropane triacrylate or trimethacrylate, pentaerythritol tetraacrylate or tetramethacrylate, bisphenol diacrylate or dimethacrylate, methylene bisacrylamide or methylene bismethacrylamide, ethylene bisacrylamide or ethylene bismethacrylate
- Another aspect of the present invention relates to a coated particle comprising a particle and a polymer coating on the surface of said particle; wherein said particle has an surface area of between about 10 nm 2 and about 30 mm 2 ; said polymer coating is represented by
- Z is selected independently for each occurrence from the group consisting of —X, —C( ⁇ O)X, —C( ⁇ O)OX, —C( ⁇ O)N(R 1 )X, —C( ⁇ O)SX, —OC( ⁇ O)X, —N(R 1 )C( ⁇ O)X, —SC( ⁇ O)X, —OX, —N(R 1 )X, —SX, —S( ⁇ O)X, and —S( ⁇ O) 2 X;
- R is selected independently for each occurrence from the group consisting of hydrogen and alkyl;
- R 1 is selected independently for each occurrence from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl;
- X is selected independently for each occurrence from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl,
- the present invention relates to the aforementioned particle, wherein R is hydrogen. In certain embodiments, the present invention relates to the aforementioned particle, wherein R is methyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein X is —(CH 2 ) n Y. In certain embodiments, the present invention relates to the aforementioned particle, wherein Y is alkyl, cycloalkyl, heterocycloalkyl, aryl, nitro, halo, hydroxyl, alkyoxy, aryloxy, amino, acylamino, amido, or carbamoyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein n is 3-8 inclusive.
- Another aspect of the present invention relates to a coated particle comprising a particle and a polymer coating on the surface of said particle; wherein said particle has an surface area of between about 10 nm 2 and about 30 mm 2 ; said polymer coating is represented by
- Z is selected independently for each occurrence from the group consisting of —C 6 (R 2 ) 5 , —C( ⁇ O)X, —C( ⁇ O)OX, and —C( ⁇ O)N(R 1 )X;
- R is selected from the group consisting of hydrogen and alkyl;
- R 1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl;
- R 2 is independently selected from the group consisting of hydrogen, alkyl, bromine, chlorine, hydroxyl, alkyoxy, aryloxy, carboxyl, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido;
- X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and
- the present invention relates to the aforementioned particle, wherein R is hydrogen. In certain embodiments, the present invention relates to the aforementioned particle, wherein R is methyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein R 1 is aralkyl or carboxyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein R2 is independently selected from the group consisting of hydrogen, alkyl, bromine and chlorine. In certain embodiments, the present invention relates to the aforementioned particle, wherein X is —(CH 2 ) n Y.
- the present invention relates to the aforementioned particle, wherein Y is alkyl, cycloalkyl, heterocycloalkyl, aryl, nitro, halo, hydroxyl, alkyoxy, aryloxy, amino, acylamino, amido, or carbamoyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein n is 3-8 inclusive.
- Another aspect of the present invention relates to a coated particle comprising a particle and a polymer coating on the surface of said particle; wherein said particle has an surface area of between about 10 nm 2 and about 30 mm 2 ; said polymer coating is represented by
- Z is selected independently for each occurrence from the group consisting of —C 6 (R 2 ) 5 , and —C( ⁇ O)OX;
- R is selected from the group consisting of hydrogen and methyl;
- R 2 is independently selected from the group consisting of hydrogen, methyl, bromine and chlorine;
- X is —(CH 2 ) n Y;
- Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; n is, independently for each occurrence, 1-10 inclusive; and m is 30-300 inclusive.
- the present invention relates to the aforementioned particle, wherein R is hydrogen. In certain embodiments, the present invention relates to the aforementioned particle, wherein R is methyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein R 2 is independently selected from the group consisting of hydrogen and methyl. In certain embodiments, the present invention relates to the aforementioned particle, wherein R 2 is independently selected from the group consisting of hydrogen and bromine. In certain embodiments, the present invention relates to the aforementioned particle, wherein R 2 is independently selected from the group consisting of hydrogen and chlorine. In certain embodiments, the present invention relates to the aforementioned particle, wherein Y is hydrogen or heterocyloalkyl.
- the present invention relates to the aforementioned particle, wherein Y is hydrogen. In certain embodiments, the present invention relates to the aforementioned particle, wherein Y is an oxirane. In certain embodiments, the present invention relates to the aforementioned particle, wherein n is 3-8 inclusive. In certain embodiments, the present invention relates to the aforementioned particle, wherein Z is selected independently for each occurrence from the group consisting of —C( ⁇ O)OH and —C( ⁇ O)OCH 2 CH 3 .
- Another aspect of the present invention relates to a coated particle comprising a particle and a polymer coating on the surface of said particle; wherein said particle has a surface area of between about 10 nm 2 and 30 mm 2 ; said polymer coating is
- Z is selected independently for each occurrence from the group consisting of —X, —C( ⁇ O)X, —C( ⁇ O)OX, —C( ⁇ O)N(R 1 )X, —C( ⁇ O)SX, —OC( ⁇ O)X, —N(R 1 )C( ⁇ O)X, —SC( ⁇ O)X, —OX, —N(R 1 )X, —SX, —S( ⁇ O)X, and —S( ⁇ O) 2 X;
- W is selected independently for each occurrence from the group consisting of—(CH 2 ) n —,
- the present invention relates to the aforementioned particle, wherein R is hydrogen or methyl.
- the present invention relates to the aforementioned particle, wherein Z is selected independently for each occurrence from the group consisting of —C 6 (R 2 ) 5 , —C( ⁇ O)X, —C( ⁇ O)OX, and —C( ⁇ O)N(R 1 )X; and R 2 is independently selected from the group consisting of hydrogen, alkyl, bromine, chlorine, hydroxyl, alkyoxy, aryloxy, carboxyl, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido.
- the present invention relates to the aforementioned particle, wherein Z is selected independently for each occurrence from the group consisting of —C 6 (R 2 ) 5 , and —C( ⁇ O)OX; R is selected from the group consisting of hydrogen and methyl; R 2 is independently selected from the group consisting of hydrogen, methyl, bromine and chlorine; X is —(CH 2 ) n Y; and Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido.
- the present invention relates to the aforementioned particle, wherein Z is —C( ⁇
- the present invention relates to the aforementioned particle, wherein said particle is selected from the group consisting of ceramics and glasses, oxides, carbides, nitrides, metals, minerals, semiconductors, polymers, carbon, magnetic particles, superconducting particles-quantum dots, fluorescent particles, colored or dyed particles, colloidal particles, microparticles, microspheres, microbeads, nanoparticles, nanospheres, nanorods, nanowires, shell particles, core particles, organic nanoparticles, and inorganic-organic hybrid nanoparticles.
- the present invention relates to the aforementioned particle, wherein said particle is selected from the group consisting of fused silica, fumed silica, soda glass, silica, alumina, zirconia, ceria, yttria, and titania, tin oxide, indium oxide, zinc oxide, boron tin oxide, boron zinc oxide, tantalum carbide (TaC), boron carbide (B 4 C), silicon carbide (SiC), titanium carbide, titanium nitride (TiN), boron nitride (B 4 N), gold (Au), silicon (Si), silver (Ag), platinum (Pi) nickel (Ni), calcium fluoride (CaF 2 ), quartz, silicon (Si), germanium (Ge), cadmium telluride (CdTd), gallium arsenide (GaAs), polystyrene, polymethylmethacrylate, latex; graphite, fullerenes,
- the present invention relates to the aforementioned particle, wherein said particle is a biologically active substance.
- the present invention relates to the aforementioned particle, wherein said particle is a biologically active substance selected from the group consisting of anabolic agents, antacids, anti-asthmatic agents, anti-cholesterolemic and anti-lipid agents, anti-coagulants, anti-convulsants, anti-diarrheals, anti-emetics, anti-infective agents, anti-inflammatory agents, anti-manic agents, anti-nauseants, anti-neoplastic agents, anti-obesity agents, anti-pyretic and analgesic agents, anti-spasmodic agents, anti-thrombotic agents, anti-uricemic agents, anti-anginal agents, antihistamines, anti-tussives, appetite suppressants, biologicals, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoi
- the present invention relates to the aforementioned particle, wherein said surface area is between about 10 nm 2 and about 30 mm 2 . In certain embodiments, the present invention relates to the aforementioned particle, wherein said surface area is between about 50 nm 2 and about 10 mm 2 . In certain embodiments, the present invention relates to the aforementioned particle, wherein said surface area is between about 100 nm 2 microns and about 1 mm 2 In certain embodiments, the present invention relates to the aforementioned particle, wherein said surface area is between about 10 nm 2 and about 1 mm 2 . In certain embodiments, the present invention relates to the aforementioned particle, wherein said surface area is between about 50 nm 2 and about 1 mm 2 .
- the present invention relates to the aforementioned particle, wherein said polymer coating has an average thickness of between about 0.1 nm and about 100 nm. In certain embodiments, the present invention relates to the aforementioned particle, wherein said polymer coating has an average thickness of between about 0.1 nm and about 50 nm. In certain embodiments, the present invention relates to the aforementioned particle, wherein said polymer coating has an average thickness of between about 0.1 nm and about 1 nm. In certain embodiments, the present invention relates to the aforementioned particle, wherein said polymer coating has an average thickness of between about 0.5 nm and about 50 nm.
- the present invention relates to the aforementioned particle, wherein said polymer coating has an average thickness of between about 1 nm and about 35 nm. In certain embodiments, the present invention relates to the aforementioned particle, wherein said polymer coating has an average thickness of between about 1 nm and about 10 nm.
- the present invention relates to the aforementioned particle, wherein said coating is of a uniform thickness. In certain embodiments, the present invention relates to the aforementioned particle, wherein said thickness does not vary by more than about 10% over the surface of the particle. In certain embodiments, the present invention relates to the aforementioned particle, wherein said thickness does not vary by more than about 5% over the surface of the particle. In certain embodiments, the present invention relates to the aforementioned particle, wherein said thickness does not vary by more than about 1% over the surface of the particle. In certain embodiments, the present invention relates to the aforementioned particle, wherein said polymer coating has a mass per surface area of between about 0.1 ⁇ g/cm 2 to about 500 ⁇ g/cm 2 .
- the present invention relates to the aforementioned particle, wherein said polymer coating has a mass per surface area of between about 0.1 ⁇ g/cm 2 to about 100 ⁇ g/cm 2 . In certain embodiments, the present invention relates to the aforementioned particle, wherein said polymer coating has a mass per surface area of between about 0.1 ⁇ g/cm 2 to about 50 ⁇ g/cm 2 . In certain embodiments, the present invention relates to the aforementioned particle, wherein said polymer coating has a mass per surface area of between about 0.1 ⁇ g/cm 2 to about 10 ⁇ g/cm 2 . In certain embodiments, the present invention relates to the aforementioned particle, wherein said polymer coating has a mass per surface area of between about 0.1 ⁇ g/cm 2 to about 5 ⁇ g/cm 2 .
- the present invention relates to the aforementioned particle, wherein said polymer coating has a dangling bond density of less than about 10 20 spins/cm 3 . In certain embodiments, the present invention relates to the aforementioned particle, wherein said polymer coating has a dangling bond density of less than about 10 18 spins/cm 3 . In certain embodiments, the present invention relates to the aforementioned particle, wherein said polymer coating has a dangling bond density of less than about 10 16 spins/cm 3 .
- Another aspect of the present invention relates to a plurality of any of the aforementioned polymer coated particles.
- the present invention relates to the aforementioned particles, wherein said plurality of coated particles are non-agglomerated.
- One aspect of the present invention relates to a method of coating a particle, comprising the steps of: placing said particle in a vessel at a pressure; optionally heating or cooling said vessel to a first temperature; rotating said vessel at a rotating speed for a period of time; mixing together a first gaseous monomer at a first flow rate, and a gaseous initiator at a second flow rate, thereby forming a mixture; introducing said mixture into said vessel via a conduit which comprises a heated filament at a second temperature; heating said mixture with said heated filament, thereby forming a reactive mixture; contacting said particle with said reactive mixture; thereby forming a polymer coating on said particle.
- One aspect of the present invention relates to a method of coating a plurality of particles, comprising the steps of: placing said particles in a vessel at a pressure; optionally heating or cooling said vessel to a first temperature; rotating said vessel at a rotating speed for a period of time; mixing together a first gaseous monomer at a first flow rate, and a gaseous initiator at a second flow rate, thereby forming a mixture; introducing said mixture into said vessel via a conduit which comprises a heated filament at a second temperature; heating said mixture with said heated filament, thereby forming a reactive mixture; contacting said particles with said reactive mixture, thereby forming polymer coatings on said particle.
- the present invention relates to the any of the aforementioned methods, further comprising mixing, with said first gaseous monomer and said gaseous initiator, a second gaseous monomer at a third flow rate.
- said second gaseous monomer is any monomer described herein
- the present invention relates to the any of the aforementioned methods, further comprising mixing, with said first gaseous monomer and said gaseous initiator, a crosslinker at a fourth flow rate.
- said crosslinker is any crosslinker described herein.
- the present invention relates to the any of the aforementioned methods, wherein the gaseous initiator is selected from the group consisting of compounds of formula I: A-X—B I wherein, A is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; X is —O—O— or —N ⁇ N—; and B is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
- the present invention relates to the any of the aforementioned methods, wherein A is alkyl.
- the present invention relates to the any of the aforementioned methods, wherein R 4 is hydrogen or alkyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein A is hydrogen. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein B is alkyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein X is —O—O—. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein X is —N ⁇ N—.
- the present invention relates to the any of the aforementioned methods, wherein A is —C(CH 3 ) 3 ; and B is —C(CH 3 ) 3 . In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein A is —C(CH 3 ) 3 ; X is —O—O—; and B is —C(CH 3 ) 3 . In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein the gaseous initiator is selected from the group consisting of hydrogen peroxide, alkyl peroxides, aryl peroxides, hydroperoxides, halogens and azo compounds.
- the present invention relates to the any of the aforementioned methods, wherein said first gaseous monomer is selected from the group consisting of
- R is selected from the group consisting of hydrogen and alkyl
- R 1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl
- X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH 2 ) n Y
- Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive.
- the present invention relates to the any of the aforementioned methods, wherein R is hydrogen. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein R is methyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein X is —(CH 2 ) n Y. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein Y is alkyl, cycloalkyl, heterocycloalkyl, aryl, nitro, halo, hydroxyl, alkyoxy, aryloxy, amino, acylamino, amido, or carbamoyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein n is 3-8 inclusive.
- the present invention relates to the any of the aforementioned methods, wherein said first gaseous monomer is selected from the group consisting of
- R is selected from the group consisting of hydrogen and alkyl;
- R 1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl;
- R 2 is independently selected from the group consisting of hydrogen, alkyl, bromine, chlorine, hydroxyl, alkyoxy, aryloxy, carboxyl, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido;
- X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH 2 ) n Y;
- Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoara
- the present invention relates to the any of the aforementioned methods, wherein R is hydrogen. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein R is methyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein R 1 is aralkyl or carboxyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein R 2 is independently selected from the group consisting of hydrogen, alkyl, bromine and chlorine. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein X is hydrogen or —(CH 2 ) n Y.
- the present invention relates to the any of the aforementioned methods, wherein Y is alkyl, cycloalkyl, heterocycloalkyl, aryl, nitro, halo, hydroxyl, alkyoxy, aryloxy, amino, acylamino, amido, or carbamoyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein n is 3-8 inclusive.
- the present invention relates to the any of the aforementioned methods, wherein said first gaseous monomer is selected from the group consisting of
- R is selected from the group consisting of hydrogen and methyl;
- R 2 is independently selected from the group consisting of hydrogen, methyl, bromine and chlorine;
- X is hydrogen or —(CH 2 ) n Y;
- Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive.
- the present invention relates to the any of the aforementioned methods, wherein R is hydrogen. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein R is methyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein R 2 is independently selected from the group consisting of hydrogen and methyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein R 2 is independently selected from the group consisting of hydrogen and bromine. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein R 2 is independently selected from the group consisting of hydrogen and chlorine.
- the present invention relates to the any of the aforementioned methods, wherein Y is hydrogen or heterocyloalkyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein Y is hydrogen. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein Y is an oxirane. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein n is 3-8 inclusive.
- the present invention relates to the any of the aforementioned methods, wherein said first gaseous monomer is selected from the group consisting of poly(glycidyl methacrylate), p-bromophenyl methacrylate, pentabromophenyl methacrylate, n-vinyl carbazole, p-divinyl benzene, styrene, alpha methyl styrene, 2-chlorostyrene, 3-chlorostyrene, 4-chlorostyrene, 2,3-dichlorostyrene, 2,4-dichlorostyrene, 2,5-dichlorostyrene, 2,6-dichlorostyrene, 3,4-dichlorostyrene, 3,5-dichlorostyrene, 2-bromostyrene, 3-bromostyrene, 4-bromostyrene, 2,3-dibromostyrene, 2,4-dibromostyrene, 2,5-dibromostyrene, 2,
- the present invention relates to the any of the aforementioned methods, wherein said particle is selected from the group consisting of ceramics and glasses, oxides, carbides, nitrides, metals, minerals, semiconductors, polymers, carbon, magnetic particles, superconducting particles-quantum dots, fluorescent particles, colored or dyed particles, colloidal particles, microparticles, microspheres, microbeads, nanoparticles, nanospheres, nanorods, nanowires, shell particles, core particles, organic nanoparticles, and inorganic-organic hybrid nanoparticles.
- the present invention relates to the any of the aforementioned methods, wherein said particle is selected from the group consisting of fused silica, fumed silica, soda glass, silica, alumina, zirconia, ceria, yttria, and titania, tin oxide, indium oxide, zinc oxide, boron tin oxide, boron zinc oxide, tantalum carbide (TaC), boron carbide (B 4 C), silicon carbide (SiC), titanium carbide, titanium nitride (TiN), boron nitride (B 4 N), gold (Au), silicon (Si), silver (Ag), platinum (Pi) nickel (Ni), calcium fluoride (CaF 2 ), quartz, silicon (Si), germanium (Ge), cadmium telluride (CdTd), gallium arsenide (GaAs), polystyrene, polymethylmethacrylate, latex; graphite, fulleren
- the present invention relates to the any of the aforementioned methods, wherein said particle is a biologically active substance.
- the present invention relates to the any of the aforementioned methods, wherein said particle is a biologically active substance selected from the group consisting of anabolic agents, antacids, anti-asthmatic agents, anti-cholesterolemic and anti-lipid agents, anti-coagulants, anti-convulsants, anti-diarrheals, anti-emetics, anti-infective agents, anti-inflammatory agents, anti-manic agents, anti-nauseants, anti-neoplastic agents, anti-obesity agents, anti-pyretic and analgesic agents, anti-spasmodic agents, anti-thrombotic agents, anti-uricemic agents, anti-anginal agents, antihistamines, anti-tussives, appetite suppressants, biologicals, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents,
- the present invention relates to the any of the aforementioned methods, wherein said pressure is atmospheric pressure. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said pressure is less than about 1 torr. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said pressure is less than about 0.7 torr. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said pressure is less than 0.4 torr. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said pressure is about 1 torr. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said pressure is about 0.7 torr. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said pressure is about 0.4 torr.
- the present invention relates to the any of the aforementioned methods, wherein said first flow rate is about 10 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said first flow rate is less than about 10 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said first flow rate is about 5 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said first flow rate is less than about 5 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said first flow rate is about 3 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said first flow rate is less than about 3 sccm.
- the present invention relates to the any of the aforementioned methods, wherein said second flow rate is about 1.5 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is less than about 1.5 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is about 0.75 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is less than about 0.75 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is about 10 sccm.
- the present invention relates to the any of the aforementioned methods, wherein said second flow rate is less than about 10 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is about 5 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is less than about 5 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is about 3 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is less than about 3 sccm.
- the present invention relates to the any of the aforementioned methods, wherein said second flow rate is about 1.5 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is less than about 1.5 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is about 0.75 sccm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second flow rate is less than about 0.75 sccm.
- the present invention relates to the any of the aforementioned methods, wherein said first temperature is about 25° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said first temperature is between about 25° C. and 100° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said first temperature is between about 0° C. and 25° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said first temperature is controlled by a water bath.
- the present invention relates to the any of the aforementioned methods, wherein said second temperature is between about 50° C. and about 350° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is between about 100° C. and about 350° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is between about 150° C. and about 350° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is between about 200° C. and about 350° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is between about 250° C. and about 350° C.
- the present invention relates to the any of the aforementioned methods, wherein said second temperature is about 350° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is about 300° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is about 250° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is about 245° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is about 235° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is about 225° C.
- the present invention relates to the any of the aforementioned methods, wherein said second temperature is about 200° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is about 150° C. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said second temperature is about 100° C.
- the present invention relates to the any of the aforementioned methods, wherein said rotating speed is about 50 rpm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said rotating speed is about 100 rpm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said rotating speed is about 150 rpm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said rotating speed is about 200 rpm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said rotating speed is about 250 rpm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said rotating speed is about 300 rpm. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said rotating speed is about 350 rpm.
- the present invention relates to the any of the aforementioned methods, wherein said pressure is 0.4 torr; said first flow rate is about 1.5 sccm; said second flow rate is about 0.2 sccm initiator flow; said second temperature is 235° C. filament temperature; said first temperature is 25° C.; and said rotating speed is about 150 rpm.
- the present invention relates to the any of the aforementioned methods, further comprising reacting said polymer coating with an electrophile. In certain embodiments, the present invention relates to the any of the aforementioned methods, further comprising reacting said polymer coating with a nucleophile. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said nucleophile is an hydroxy-containing compound, amine-containing compound or thiol-containing compound. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said nucleophile is an organometallic compound. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said nucleophile is an amine-containing compound.
- the present invention relates to the any of the aforementioned methods, wherein said nucleophile is fluorescent. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein said nucleophile is fluorecein-5-thiosemicarbazide.
- One aspect of the present invention relates to an apparatus for depositing a polymer coatings on a plurality of particles comprising a rotating vessel; a vapor feedline for delivering vapors into said rotating vessel through exit holes; and a filament wire in proximity to said exit holes.
- the present invention relates to the aforementioned apparatus, wherein said vapor feedline further comprises an in-line sheathed heater. In certain embodiments, the present invention relates to the aforementioned apparatus, wherein said vapor feedline is stainless steel. In certain embodiments, the present invention relates to the aforementioned apparatus, wherein said exit holes are substantially evenly spaced. In certain embodiments, the present invention relates to the aforementioned apparatus, wherein said filament wire is a coiled filament wire. In certain embodiments, the present invention relates to the aforementioned apparatus, wherein said rotating vessel is glass. In certain embodiments, the present invention relates to the aforementioned apparatus, further comprising a temperature-controlled bath for controlling the temperature of the rotating vessel.
- the present invention relates to the aforementioned apparatus, further comprising a flow control system to control the flow of said vapors. In certain embodiments, the present invention relates to the aforementioned apparatus, further comprising a pressure control system. In certain embodiments, the present invention relates to the aforementioned apparatus, wherein said pressure control system comprises a dry pump system.
- Another aspect of the present invention relates to an apparatus for depositing a polymer coatings on a plurality of particles comprising a vessel; a means for rotating said vessel; a means for introducing vapors into said vessel; and a means for heating said vapors.
- the present invention relates to the aforementioned apparatus, further comprising a means for controlling the temperature of said vessel.
- the present invention relates to the aforementioned apparatus, further comprising a means for controlling the pressure in said vessel.
- the iCVD setup can be configured in different ways. It can be set up as a one-dimensional flow-through system that has been detailed elsewhere (e.g., FIG. 7 ). It can alternatively be set up to allow particle agitation using a rotary mechanism to create a rotating particle bed (e.g., FIG. 8 ).
- glycidyl methacrylate (Aldrich) and tert-amyl peroxide (Aldrich) were used as-received and fed into the coating chamber at 3.0 and 0.3 sccm, respectively, using precision mass flow controllers (MKS Instruments).
- MKS Instruments precision mass flow controllers
- Vacuum was achieved by a dry pump (iQDP40, BOC Edwards) and a roots blower (WAU-150, Leybold).
- the initiator was thermally activated using electrically resistive wires heated to 250° C. by a DC power supply (DHP 150-20 Sorensen).
- a water bath at 30° C. provided cooling to the particle bed to promote adsorption of active species and monomer vapor for polymerization.
- sodalime glass microspheres 25-32 ⁇ m diameter, Whitehouse Scientific
- Fourier transform infrared spectroscopy made use of a Thermo Nicolet NEXUS 870 equipped with a DTGS detector.
- the nanotubes were compressed into KBr pellets and spectra were acquired at 4 cm ⁇ 1 resolution for 64 scans.
- Transmission electron microscopy was performed on a JEOL 200 CX at 200 kV.
- the nanotubes were mounted on Cu grids with a Formvar support stabilized with carbon.
- X-ray photoelectron spectroscopy was done on a Kratos AXIS Ultra using a monochromatic Al anode at 150 W with charge neutralization. Samples were mounted by pressing the microspheres onto a copper adhesive tape.
- Hexamethylenediamine (Aldrich) was dissolved in neat ethanol (Aldrich) to form a 0.5 M solution.
- a vial containing 20 mg of PGMA-coated microspheres in 5 ml of the 0.5 M hexamethylenediamine solution was placed in a 60° C. water bath for 5 h. The microspheres were then isolated and washed 5 times with ethanol to remove any unreacted amine.
- 50 mg of fluorescein-5-thiosemicarbazide (Molecular Probes, Invitrogen) were dissolved in 10 ml of pH 8.0 phosphate buffer.
- a vial containing 20 mg of PGMA-coated microspheres in 5 ml buffer was placed in a 60° C.
- PGMA-coated microspheres were soaked in 3 ml of tetrahydrofuran (J T Baker) to dissolve the coating into solution, after which 1 ml of the solution was filtered through a 0.45 ⁇ m PTFE filter and injected into the GPC column. Based on the calibration curve, the area of the GPC trace then allowed the PGMA concentration and mass of PGMA in the 3 ml solution to be determined.
- the PGMA density to be 1 g/cm 3 and the microsphere diameter and density as 28.5 ⁇ m and 2.46 g/cm 3 , respectively, the thickness of PGMA on each particle was calculated.
- FIG. 11 shows a series of Fourier transform infrared (FTIR) spectra of poly(methacrylic acid-co-ethyl acrylate) coatings produced via iCVD and one of a USP Type C methacrylic acid copolymer, Eudragit L 100-55, obtained from Röhm.
- FTIR is specified by the USP as a primary form of identification for methacrylic acid copolymers.
- the two FTIR peaks centered around 1735 and 1700 cm ⁇ 1 are assigned as the carbonyl peak of the ethyl acrylate unit and methacrylic acid unit, respectively.
- Ibuprofen drug particles is coated with a USP Type C methacrylic acid copolymer which is a poly(methacrylic acid-co-ethyl acrylate) in a 1:1 ratio.
- This composition has already been proven to be attainable using a CVD process (as reported herein).
- the copolymer properties that are required are specified in the USP/NF official monograph and are given in Table 1 below. [Methacrylic acid copolymer. In USP-NF pp. 2791-2792 (United States Pharmacopeial Convention, Inc., Rockville, Md., 2003).]
- Enteric Coating Thickness A sufficient thickness of coating is required to achieve the proper enteric function, provide a sufficient barrier layer to protect against environments below a pH of 6-7, and eliminate any pinholes which may lead to premature coating failure.
- the coating thickness required one can look at the values for the methacrylic acid copolymers used in solvent-based coating methods. For the Eudragits, Röhm recommends a minimum polymer loading of 1-2 mg/cm 2 (polymer dry weight per drug surface area). Assuming a polymer density of 1 g/cm 3 , the minimum polymer thickness required is calculated as a function of drug particle size, assuming that the particle is essentially spherical, this is shown in FIG. 13 . For a particle of size between 20-35 ⁇ m, a minimum coating thickness is on the order of 5-10 ⁇ m, while a particle of size between 5-10 ⁇ m would need a thickness of 3-6 ⁇ m.
- FIG. 14 shows the time for the polymer coating to disintegrate as a function of initial polymer coating thickness for two pH environments, one at pH 1.2 to simulate gastric fluid and one at pH 6.8 to simulate intestinal fluid.
- the disintegration time at pH 1.2 should be at least 2 hours, which is the normal time for the drug to pass through the upper gastrointestinal tract and into the duodenum
- the disintegration time at pH 6.8 should be minimal since the drug core needs to be exposed for the drug to dissolve and get absorbed by the intestines.
- coating thickness greater than 2 ⁇ m is estimated to be sufficient for enteric function, this agrees reasonably well with the estimates based on the Eudragit recommendations.
- Level B1 6 tested tablets each unit ⁇ 80% dissolved Level B2 6 tested tablets, average of B1 and B2 ⁇ 75% dissolved and no individual unit ⁇ 60% dissolved
- Level B3 12 tested tablets average of B1, B2 and B3 ⁇ 75% dissolved, not more than 2 units ⁇ 60%, and no unit ⁇ 50% dissolved
- Coating composition and structure are characterized using FTIR and 1 H solution NMR.
- a one-to-one molar ratio of methacrylic acid and ethyl acrylate units is required for the USP Type C copolymer.
- Acid value of the methacrylic acid copolymers will also be determined by titrimetry according to the USP 541 protocol. [ ⁇ 541> Titrimetry. In USP-NF pp. 2229-2232 (United States Pharmacopeial Convention, Inc., Rockville, Md., 2003).] Molecular weight and MW distribution is determined using gel permeation chromatography (GPC), Röhm reports their Eudragit material to be approximately 250,000 MW.
- DSC Differential scanning calorimetry
- Coating thickness on ibuprofen particles is measured using SEM by analyzing the size of the particles before and after coating treatment. SEM will also provide information on coating uniformity and conformality, whether individual particles have been effectively coated. Mechanical sieving is used to identify any particle agglomeration from the coating process, particles will be sieved to determine the minimum sieve size which the particles can pass through, minimal shaking force will prevent any false negatives from agglomerate breakup due to sieving. Determining the coating thickness will allow deposition rates to be calculated and the iCVD process optimized for rapid coating, based on optimizing CVD reactor variables such as reactor pressure, reactant flow rates, and the activation temperature. [ ⁇ 231> Heavy metals.
- iCVD Copolymerization The iCVD described below was performed using continuous flow reactors which are capable of depositing on silicon flats and around three-dimensional particles.
- polymerization utilized methacrylic acid (Aldrich, 99%) and ethyl acrylate (Aldrich, 99%) as the comonomers, and tert-butyl peroxide (Aldrich, 98%) as the radical initiator. All reactants were used as received.
- the MAA source vessel was heated to 70° C. to enable sufficient vapor flow.
- F MAA 0.15, 0.59, 0.68, 1.03 and 1.47 sccm
- F EA 20.8 sccm
- F TBPO 0.80 sccm
- T filament 260° C.
- T substrate 25° C.
- FTIR was carried out on a Thermo Nicolet NEXUS 870 equipped with a DTGS detector and KBr beam splitter. Spectra were acquired at 4 cm ⁇ 1 resolution for 64 scans.
- XPS made use of a Kratos AXIS Ultra with a 150 W monochromatized Al source and charge neutralization. Characterizations were made on methacrylic acid copolymers deposited on silicon substrates. Additionally, GPC was performed on a P(MAA-EA) copolymer using a Waters Breeze system with Styragel HR columns and tetrahydrofuran (JT Baker, HPLC grade) as the elution solvent.
- the copolymer sample was dissolved off the silicon wafer using THF prior to analysis.
- Molecular weight and molecular weight distribution were determined against a calibration from a set of narrow poly(methyl methacrylate) standards.
- M n and PDI were determined to be 8,900 g.mol ⁇ 1 and 2.24, respectively.
- Release Measurements Release in various pH buffers was traced by measuring changes in light absorption over time. For fluorescein, release was monitored at 490 nm, comparing fluorescein layered on silicon substrates that were exposed or encapsulated with an iCVD P(MAA-EDMA) coating. For ibuprofen, 25 ⁇ m ibuprofen microcrystals (DuPont), that were bare or encapsulated with an iCVD P(MAA-EDMA) coating, were compressed into pellets and their release monitored at 220 nm. Absorption was measured on a Varian Cary 6000i.
Abstract
Description
A-X—B I
wherein, independently for each occurrence, A is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; X is —O—O— or —N═N—; and B is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
wherein, independently for each occurrence: R is selected from the group consisting of hydrogen and alkyl; R1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl; X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH2)nY; Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive. The term “copolymer” as used herein means a polymer of two or more different monomers.
wherein R50, R51, R52 and R53 each independently represent a hydrogen, an alkyl, an alkenyl, —(CH2)m—R61, or R50 and R51 or R52, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or —(CH2)m—R61. Thus, the term “alkylamine” includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or —(CH2)m—R61, where m and R61 are as defined above.
wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.
wherein X50 is a bond or represents an oxygen or a sulfur, and R55 and R56 represents a hydrogen, an alkyl, an alkenyl, —(CH2)m—R61 or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or —(CH2)m—R61, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an “ester”. Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a “carboxylic acid”. Where X50 is an oxygen, and R56 is hydrogen, the formula represents a “formate”. In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a “thiolcarbonyl” group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a “thiolester.” Where X50 is a sulfur and R55 is hydrogen, the formula represents a “thiolcarboxylic acid.” Where X50 is a sulfur and R56 is hydrogen, the formula represents a “thiolformate.” On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a “ketone” group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an “aldehyde” group.
wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or —(CH2)m—R61. The moiety is an “oxime” when R is H; and it is an “oxime ether” when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or —(CH2)m—R61.
in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
R is selected from the group consisting of hydrogen and alkyl; R1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl; X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH2)nY; Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive.
R is selected from the group consisting of hydrogen and alkyl; R1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl; R2 is independently selected from the group consisting of hydrogen, alkyl, bromine, chlorine, hydroxyl, alkyoxy, aryloxy, carboxyl, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH2)nY; Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive.
R is selected from the group consisting of hydrogen and methyl; R2 is independently selected from the group consisting of hydrogen, methyl, bromine and chlorine; X is hydrogen or —(CH2)nY; Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive.
Z is selected independently for each occurrence from the group consisting of —X, —C(═O)X, —C(═O)OX, —C(═O)N(R1)X, —C(═O)SX, —OC(═O)X, —N(R1)C(═O)X, —SC(═O)X, —OX, —N(R1)X, —SX, —S(═O)X, and —S(═O)2X; R is selected independently for each occurrence from the group consisting of hydrogen and alkyl; R1 is selected independently for each occurrence from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl; X is selected independently for each occurrence from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH2)nY; Y is selected independently for each occurrence from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; n is, independently for each occurrence, 1-10 inclusive; and m is 30-300 inclusive.
Z is selected independently for each occurrence from the group consisting of —C6(R2)5, —C(═O)X, —C(═O)OX, and —C(═O)N(R1)X; R is selected from the group consisting of hydrogen and alkyl; R1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl; R2 is independently selected from the group consisting of hydrogen, alkyl, bromine, chlorine, hydroxyl, alkyoxy, aryloxy, carboxyl, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH2)nY; Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; n is, independently for each occurrence, 1-10 inclusive; and m is 30-300 inclusive.
Z is selected independently for each occurrence from the group consisting of —C6(R2)5, and —C(═O)OX; R is selected from the group consisting of hydrogen and methyl; R2 is independently selected from the group consisting of hydrogen, methyl, bromine and chlorine; X is —(CH2)nY; Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; n is, independently for each occurrence, 1-10 inclusive; and m is 30-300 inclusive.
Z is selected independently for each occurrence from the group consisting of —X, —C(═O)X, —C(═O)OX, —C(═O)N(R1)X, —C(═O)SX, —OC(═O)X, —N(R1)C(═O)X, —SC(═O)X, —OX, —N(R1)X, —SX, —S(═O)X, and —S(═O)2X; W is selected independently for each occurrence from the group consisting of—(CH2)n—,
C(═O)—(CH2)n—C(═O)—, —OC(═O)—(CH2)n—C(═O)O—, —N(R1)C(═O)—(CH2)n—C(═O)N(R1)—, —SC(═O)—(CH2)n—C(═O)S—, —C(═O)O—(CH2)n—OC(═O)—, —C(═O)N(R1)—(CH2)n—N(R1)C(═O)—, —C(═O)S—(CH2)n—SC(═O)—, —O—(CH2)n—O—, —N(R1)—(CH2)n—N(R1)— and —S—(CH2)n—S—; R1 is selected independently for each occurrence from the group consisting of hydrogen and alkyl; R1 is selected independently for each occurrence from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl; X is selected independently for each occurrence from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH2)nY; Y is selected independently for each occurrence from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; p is, independently for each occurrence, 0 or 1; q is, independently for each occurrence, 0 or 1; n is 1-10 inclusive; and m is 30-300 inclusive.
A-X—B I
wherein, A is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; X is —O—O— or —N═N—; and B is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein A is alkyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein R4 is hydrogen or alkyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein A is hydrogen. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein B is alkyl. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein X is —O—O—. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein X is —N═N—. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein A is —C(CH3)3; and B is —C(CH3)3. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein A is —C(CH3)3; X is —O—O—; and B is —C(CH3)3. In certain embodiments, the present invention relates to the any of the aforementioned methods, wherein the gaseous initiator is selected from the group consisting of hydrogen peroxide, alkyl peroxides, aryl peroxides, hydroperoxides, halogens and azo compounds.
R is selected from the group consisting of hydrogen and alkyl; R1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl; X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH2)nY; Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive.
R is selected from the group consisting of hydrogen and alkyl; R1 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl, and carboxyl; R2 is independently selected from the group consisting of hydrogen, alkyl, bromine, chlorine, hydroxyl, alkyoxy, aryloxy, carboxyl, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; X is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, and —(CH2)nY; Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive.
R is selected from the group consisting of hydrogen and methyl; R2 is independently selected from the group consisting of hydrogen, methyl, bromine and chlorine; X is hydrogen or —(CH2)nY; Y is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteoaralkyl, nitro, halo, hydroxyl, alkyoxy, aryloxy, carboxyl, heteroaryloxy, amino, acylamino, amido, carbamoyl, sulfhydryl, sulfonate, and sulfoxido; and n is 1-10 inclusive.
TABLE 1 |
Specifications on USP Type C methacrylic acid copolymer. |
Poly(methacrylic acid-co-ethyl acrylate) | 1:1 molar ratio |
Assay of methacrylic acid units | 46.0-50.6% on a dried basis |
Heavy metals | max. 0.002% |
Monomers | max. 0.05% |
Residue on ignition | max. 0.4% |
Acid value | 300-330 mg KOH/g polymer |
Density | 0.8-1.1 g/cm3 |
TABLE 2 |
Dissolution target levels specified in the |
USP 724 Drug Release test protocol for enteric-coated articles. |
pH 1.2 | 0.1 N HCl for 2 h at 37 ± 0.5° |
Level A1 | |
6 tested tablets, no individual tablet >10% dissolved | |
|
6 tested tablets, average of A1 and A2 ≦10% dissolved |
and no individual unit >25% dissolved | |
|
12 tested tablets, average of A1, A2 and A3 ≦10% dissolved |
and no individual unit >25% dissolved | |
pH 6.8 | Buffered phosphate solution for 45 min at 37 ± 0.5° |
Level B1 | |
6 tested tablets, each unit ≧80% dissolved | |
|
6 tested tablets, average of B1 and B2 ≧75% dissolved and |
no individual unit <60% dissolved | |
|
12 tested tablets, average of B1, B2 and B3 ≧75% dissolved, |
not more than 2 units <60%, and no unit <50% dissolved | |
Claims (20)
A-X—B I
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/589,683 US9492805B2 (en) | 2005-11-01 | 2006-10-30 | Initiated chemical vapor deposition of vinyl polymers for the encapsulation of particles |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US73237105P | 2005-11-01 | 2005-11-01 | |
US11/589,683 US9492805B2 (en) | 2005-11-01 | 2006-10-30 | Initiated chemical vapor deposition of vinyl polymers for the encapsulation of particles |
Publications (2)
Publication Number | Publication Date |
---|---|
US20070104860A1 US20070104860A1 (en) | 2007-05-10 |
US9492805B2 true US9492805B2 (en) | 2016-11-15 |
Family
ID=38707272
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/589,683 Active 2030-10-05 US9492805B2 (en) | 2005-11-01 | 2006-10-30 | Initiated chemical vapor deposition of vinyl polymers for the encapsulation of particles |
Country Status (2)
Country | Link |
---|---|
US (1) | US9492805B2 (en) |
WO (1) | WO2007145657A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9951419B2 (en) * | 2011-09-03 | 2018-04-24 | Ying-Bing JIANG | Apparatus and method for making atomic layer deposition on fine powders |
US11371143B2 (en) | 2019-05-31 | 2022-06-28 | International Business Machines Corporation | Implementing the post-porosity plasma protection (P4) process using I-CVD |
US20230080524A1 (en) * | 2021-08-24 | 2023-03-16 | Industry-Academic Cooperation Foundation | Pharmaceutical composition for treating inflammatory diseases comprising germanium telluride nanosheets coated with polyvinylpyrrolidone |
Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060045822A1 (en) | 2004-09-01 | 2006-03-02 | Board Of Regents, The University Of Texas System | Plasma polymerization for encapsulating particles |
US20100297251A1 (en) * | 2004-09-01 | 2010-11-25 | Board Of Regents, The University Of Texas System | Encapsulated particles for enteric release |
GB0708293D0 (en) * | 2007-04-28 | 2007-06-06 | Q Flo Ltd | An enhancement of the structure and properties of carbon nanotube fibres |
JP2010530912A (en) * | 2007-06-22 | 2010-09-16 | フィオ コーポレイション | Manufacturing system and method for polymer microbeads doped with quantum dots |
US20090087562A1 (en) * | 2007-09-27 | 2009-04-02 | Long Hua Lee | Method of preparing cross-linked organic glasses for air-gap sacrificial layers |
FR2926473B1 (en) * | 2008-01-22 | 2012-07-27 | Commissariat Energie Atomique | COATED AND FUNCTIONALIZED PARTICLES, POLYMER CONTAINING THEM, PROCESS FOR PREPARING THEM AND USES THEREOF |
US8088451B2 (en) | 2008-03-13 | 2012-01-03 | Board Of Regents, The University Of Texas System | Covalently functionalized particles for synthesis of new composite materials |
SI22751A (en) * | 2008-04-03 | 2009-10-31 | Krka, D.D., Novo Mesto | Toltrazuril with improved dissolution properties |
WO2009143373A1 (en) * | 2008-05-21 | 2009-11-26 | Triton Systems, Inc. | Detection of peroxide radicals and reaction initiators |
US8765238B2 (en) * | 2009-03-18 | 2014-07-01 | Boston Scientific Scimed, Inc. | Polymeric/inorganic composite materials for use in medical devices |
WO2010111084A2 (en) * | 2009-03-24 | 2010-09-30 | Drexel University | Poly(ethylene glycol) and poly(ethylene oxide) by initiated chemical vapor deposition |
WO2011146077A1 (en) * | 2010-05-21 | 2011-11-24 | Board Of Regents, The University Of Texas System | Encapsulated particles for amorphous stability enhancement |
US20120058302A1 (en) * | 2010-09-03 | 2012-03-08 | Massachusetts Institute Of Technology | Fabrication of anti-fouling surfaces comprising a micro- or nano-patterned coating |
WO2012116814A1 (en) * | 2011-03-03 | 2012-09-07 | Merck Patent Gmbh | Coated solid pharmaceutical preparation |
US8357896B2 (en) * | 2011-03-09 | 2013-01-22 | Humboldt-Universitat Zu Berlin | Method of analyzing a substance |
JP6008962B2 (en) | 2011-07-08 | 2016-10-19 | ピーエスティ・センサーズ・(プロプライエタリー)・リミテッドPst Sensors (Proprietary) Limited | Method for producing nanoparticles |
CN102500342B (en) * | 2011-10-19 | 2013-07-24 | 北京工业大学 | Method for loading organic microspheres on porous ceramic support |
CN102600773B (en) * | 2012-01-16 | 2013-12-25 | 黑龙江大学 | Method for preparing shell fluorescent microsphere |
US20130244008A1 (en) * | 2012-03-16 | 2013-09-19 | Massachusetts Institute Of Technology | Nanoporous to Solid Tailoring of Materials via Polymer CVD into Nanostructured Scaffolds |
WO2013152068A1 (en) * | 2012-04-03 | 2013-10-10 | Gvd Corporation | Adhesion promotion of vapor deposited films |
CN103818990B (en) * | 2012-11-16 | 2017-05-10 | 江南大学 | Magnetic modified sodium alginate flocculating agent |
US9656294B2 (en) * | 2012-11-20 | 2017-05-23 | Massachusetts Institute Of Technology | Fabrication and passivation of silicon surfaces |
US8962067B2 (en) * | 2013-01-24 | 2015-02-24 | Tokyo Electron Limited | Real time process control of the polymer dispersion index |
CN104788952B (en) * | 2014-01-22 | 2017-04-26 | 清华大学 | Preparation method of carbon nanotube composite structure |
CN105200395B (en) * | 2014-06-18 | 2017-11-03 | 中微半导体设备(上海)有限公司 | Air inlet and cooling device for MOCVD device |
CN105660620B (en) * | 2016-01-13 | 2018-01-26 | 南昌航空大学 | A kind of preparation method of embedded silver nano-grain carbosphere |
CN105536660B (en) * | 2016-01-15 | 2017-12-01 | 南昌航空大学 | A kind of preparation method of nano-silver loaded oil-tea camellia husks pyrolysis carbosphere |
CN105911047A (en) * | 2016-04-01 | 2016-08-31 | 河南工业大学 | Method for detecting cholesterol based on gold-silver core-shell nanoparticle colourimetry |
CN105937024A (en) * | 2016-04-20 | 2016-09-14 | 叶羽敏 | Preparation method and application of electronic product protective coating |
US10755942B2 (en) * | 2016-11-02 | 2020-08-25 | Massachusetts Institute Of Technology | Method of forming topcoat for patterning |
US11045833B2 (en) * | 2017-02-03 | 2021-06-29 | Massachusetts Institute Of Technology | Task specific ionic liquid-impregnated polymeric surface coatings for antibacterial, antifouling, and metal scavenging activity |
CN106975506B (en) * | 2017-03-14 | 2019-12-06 | 上海大学 | Boron nitride composite mesoporous oxide nickel-based catalyst and preparation method thereof |
WO2019108680A1 (en) * | 2017-11-29 | 2019-06-06 | Sirrus, Inc. | Initiated chemical vapor deposition of 1,1 disubstituted alkene compounds |
US11408074B2 (en) * | 2018-01-10 | 2022-08-09 | Lawrence Livermore National Security, Llc | Liquid-free, polymeric reinforcement of nanoscale assemblies |
CN109134721B (en) * | 2018-08-28 | 2021-03-05 | 武汉轻工大学 | Magnetic graphite/polystyrene pellet for reducing polymerization inhibition and preparation method thereof |
CN111849218B (en) * | 2019-04-26 | 2021-12-24 | 深圳先进技术研究院 | Surface modification method of material, modified material, application and medical product |
TWI729945B (en) * | 2020-10-06 | 2021-06-01 | 天虹科技股份有限公司 | Atomic layer deposition apparatus for coating on fine powders |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4810524A (en) * | 1982-06-18 | 1989-03-07 | Tdk Corporation | Inorganic powders with improved dispersibility |
US4973064A (en) * | 1989-04-26 | 1990-11-27 | Nippon Seiko Kabushiki Kaisha | Magnetic fluid seal device |
US5061630A (en) * | 1988-05-13 | 1991-10-29 | Agrogen Foundation, Seyffer & Co. & Ulrich C. Knopf | Laboratory apparatus for optional temperature-controlled heating and cooling |
US5795922A (en) * | 1995-06-06 | 1998-08-18 | Clemson University | Bone cement composistion containing microencapsulated radiopacifier and method of making same |
WO2002075309A1 (en) | 2001-03-20 | 2002-09-26 | Aviva Biosciences Corporation | Processes for producing coated magnetic microparticles and uses thereof |
WO2002096474A1 (en) | 2001-05-30 | 2002-12-05 | Tecres S.P.A. | Bone cement containing coated radiopaque particles and its preparation |
US20030026989A1 (en) | 2000-06-21 | 2003-02-06 | George Steven M. | Insulating and functionalizing fine metal-containing particles with conformal ultra-thin films |
US6613383B1 (en) | 1999-06-21 | 2003-09-02 | Regents Of The University Of Colorado | Atomic layer controlled deposition on particle surfaces |
US20040132859A1 (en) * | 2001-01-26 | 2004-07-08 | Puckett Jr Aaron D. | Bone cement and a system for mixing and delivery thereof |
JP2005149764A (en) | 2003-11-11 | 2005-06-09 | Sekisui Chem Co Ltd | Covered conductive particle, anisotropic conductive material, and conductive connection structure |
JP2005200643A (en) | 2003-12-15 | 2005-07-28 | Rikogaku Shinkokai | Method for manufacturing polymer-coated minute particles and polymer-coated minute particles |
US20070032620A1 (en) | 2005-08-05 | 2007-02-08 | Massachusetts Institute Of Technology | Chemical vapor deposition of hydrogel films |
-
2006
- 2006-10-30 WO PCT/US2006/042169 patent/WO2007145657A2/en active Application Filing
- 2006-10-30 US US11/589,683 patent/US9492805B2/en active Active
Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4810524A (en) * | 1982-06-18 | 1989-03-07 | Tdk Corporation | Inorganic powders with improved dispersibility |
US5061630A (en) * | 1988-05-13 | 1991-10-29 | Agrogen Foundation, Seyffer & Co. & Ulrich C. Knopf | Laboratory apparatus for optional temperature-controlled heating and cooling |
US4973064A (en) * | 1989-04-26 | 1990-11-27 | Nippon Seiko Kabushiki Kaisha | Magnetic fluid seal device |
US5795922A (en) * | 1995-06-06 | 1998-08-18 | Clemson University | Bone cement composistion containing microencapsulated radiopacifier and method of making same |
US6613383B1 (en) | 1999-06-21 | 2003-09-02 | Regents Of The University Of Colorado | Atomic layer controlled deposition on particle surfaces |
US20030026989A1 (en) | 2000-06-21 | 2003-02-06 | George Steven M. | Insulating and functionalizing fine metal-containing particles with conformal ultra-thin films |
US6913827B2 (en) | 2000-06-21 | 2005-07-05 | The Regents Of The University Of Colorado | Nanocoated primary particles and method for their manufacture |
US20040132859A1 (en) * | 2001-01-26 | 2004-07-08 | Puckett Jr Aaron D. | Bone cement and a system for mixing and delivery thereof |
WO2002075309A1 (en) | 2001-03-20 | 2002-09-26 | Aviva Biosciences Corporation | Processes for producing coated magnetic microparticles and uses thereof |
US20050009002A1 (en) | 2001-03-20 | 2005-01-13 | Depu Chen | Processes for producing coated magnetic microparticles and uses thereof |
WO2002096474A1 (en) | 2001-05-30 | 2002-12-05 | Tecres S.P.A. | Bone cement containing coated radiopaque particles and its preparation |
US20040157952A1 (en) * | 2001-05-30 | 2004-08-12 | Renzo Soffiati | Bone cement containing coated radiopaque particles and its preparation |
JP2005149764A (en) | 2003-11-11 | 2005-06-09 | Sekisui Chem Co Ltd | Covered conductive particle, anisotropic conductive material, and conductive connection structure |
JP2005200643A (en) | 2003-12-15 | 2005-07-28 | Rikogaku Shinkokai | Method for manufacturing polymer-coated minute particles and polymer-coated minute particles |
US20070032620A1 (en) | 2005-08-05 | 2007-02-08 | Massachusetts Institute Of Technology | Chemical vapor deposition of hydrogel films |
Non-Patent Citations (19)
Title |
---|
Cleland, J. L. et al., "Recombinant human growth hormone poly(lactic-co-glycolic acid) microsphere formulation development", Advanced Drug Delivery Reviews, 28:71-84 (Elsevier Science B.V., 1997). |
Deumie, C. et al., "Overcoated microspheres for specific optical powders", Applied Optics, 41(16):3299-3305 (Optical Society of America, 2002). |
Guignon B., et al., "Fluid Bed Encapsulation of Particles: Principles and Practice", Drying Technology, 20(2):419-447 (Marcel Dekker, Inc., 2002). |
Jiang et al., Close pacing of polymer-coated monodisperse silica, Journal of Materials Science Letters, 9 (1990), 1272-1273. * |
Kage, H. et al., "Effect of solid circulation rate on coating efficiency and agglomeration in circulating fluidized bed type coater", Powder Technology, 130:203-210 (Elsevier Science B.V., 2003). |
Lau, K. K. S. et al., "Initiated Chemical Vapor Deposition (iCVD) of Poly(alkyl acrylates): A Kinetic Model", Macromolecules, 39:3695-3703 (American Chemical Society, 2006). |
Lau, K. K. S. et al., "Initiated Chemical Vapor Deposition (iCVD) of Poly(alkyl acrylates): An Experimental Study", Macromolecules, 39:3688-3694 (American Chemical Society, 2006). |
Lau, K. K. S. et al., "Particle Surface Design using an All-Dry Encapsulation Method", Adv. Mater., 18:1972-1977 (Wiley-VCH Verlag Gmbh, Weinheim, 2006). |
Lee, J. Y. et al., "Hydrogen Bonding in Polymer Blends. 3. Blends Involving Polymers Containing Methacrylic Acid and Ether Groups", Macromolecules, 21:346-354 (American Chemical Society, 1988). |
Link, K. C. et al., "Fluidized bed spray granulation Investigation of the coating process on a single sphere", Chemical Engineering and Processing, 36(6):443-456 (Elsevier Science S. A., 1997). |
Mao et al., Hot Filament Chemical Vapor Deposition of Poly(glycidyl methacrylate) Thin Films Using tert-Butyl Peroxide as an Initiator, Langmuir (2004), 20, 2484-2488. * |
Mao, Y. et al., "Hot Filament Chemical Vapor Deposition of Poly(glycidylmethacrylate) Thin Films Using tert-Butyl Peroxide as an Initiator," Langmuir, 20:2484-2488 (American Chemical Society, 2004). |
Mengel, C. et al., Preparation and Modification of Poly(methacrylic acid) and Poly(acrylic acid) Multilayers, Langmuir, 18:6365-6372 (American Chemical Society, 2002). |
Okada, H., "One- and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate", Advanced Drug Delivery Reviews, 28:43-70 (Elsevier Science B.V., 1997). |
Partial International Search Report dated Apr. 4, 2008. |
Shi, D. et al., "Plasma deposition of Ultrathin polymer films on carbon nanotubes", Applied Physics Letters, 81(27):5216-5218 (American Institute of Physics, 2002). |
Susut, C. et al., "Plasma enhanced chemical vapor depositions to encapsulate crystals in thin polymeric films: a new approach to controlling drug release rates", Int. Journ. of Pharmac., 288:253-261 (Elsevier B.V., 2004). |
Vollath, D. et al., "Coated nanoparticles: A new way to improved nanocomposites", Journal of Nanoparticle Research, 1:235-242 (Kluwer Academic Publishers, Netherlands, 1999). |
Zeng et al., Preparation of Epoxy-Functionalized Polystyrene/Silica Core-Shell Composite Nanoparticles, Journal of Polymer Science (Mar. 25, 2004), pp. 2253-2262. * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9951419B2 (en) * | 2011-09-03 | 2018-04-24 | Ying-Bing JIANG | Apparatus and method for making atomic layer deposition on fine powders |
US11371143B2 (en) | 2019-05-31 | 2022-06-28 | International Business Machines Corporation | Implementing the post-porosity plasma protection (P4) process using I-CVD |
US20230080524A1 (en) * | 2021-08-24 | 2023-03-16 | Industry-Academic Cooperation Foundation | Pharmaceutical composition for treating inflammatory diseases comprising germanium telluride nanosheets coated with polyvinylpyrrolidone |
US11896609B2 (en) * | 2021-08-24 | 2024-02-13 | Industry-Academic Cooperation Foundation | Pharmaceutical composition for treating inflammatory diseases comprising germanium telluride nanosheets coated with polyvinylpyrrolidone |
Also Published As
Publication number | Publication date |
---|---|
US20070104860A1 (en) | 2007-05-10 |
WO2007145657A3 (en) | 2008-09-25 |
WO2007145657A2 (en) | 2007-12-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9492805B2 (en) | Initiated chemical vapor deposition of vinyl polymers for the encapsulation of particles | |
Walke et al. | Fabrication of chitosan microspheres using vanillin/TPP dual crosslinkers for protein antigens encapsulation | |
EP2342247B1 (en) | Method for preparing molecular imprint polymers (pem) by radical polymerisation | |
Kim et al. | Bioadhesive interaction and hypoglycemic effect of insulin-loaded lectin–microparticle conjugates in oral insulin delivery system | |
Qi et al. | Determination of the bioavailability of biotin conjugated onto shell cross-linked (SCK) nanoparticles | |
Arnold et al. | Utilizing click chemistry to design functional interfaces through post-polymerization modification | |
Huang et al. | Surface-initiated thermal radical polymerization on gold | |
Trujillo et al. | Grafted functional polymer nanostructures patterned bottom-up by colloidal lithography and initiated chemical vapor deposition (iCVD) | |
Kulkarni et al. | Glutaraldehyde‐crosslinked chitosan beads for controlled release of diclofenac sodium | |
SG173455A1 (en) | Hollow silica particle with a polymer thereon | |
US8496997B2 (en) | Process for the preparation of a cross-linked multilayer film | |
Chen et al. | Synthesis and Characterization of Gold− Silica Nanoparticles Incorporating a Mercaptosilane Core-Shell Interface | |
Amin et al. | Febuxostat loaded β-cyclodextrin based nanosponge tablet: An in vitro and in vivo evaluation | |
Seo et al. | Covalently bonded layer-by-layer assembly of multifunctional thin films based on activated esters | |
Mao et al. | Development of microspheres based on thiol-modified sodium alginate for intestinal-targeted drug delivery | |
Jain et al. | Lectin conjugated gastro-retentive microspheres of amoxicillin for effective treatment of Helicobacter pylori | |
Delgado et al. | Engineering thiolated surfaces with polyelectrolyte multilayers | |
Li et al. | Double-shelled polymer nanocontainers decorated with poly (ethylene glycol) brushes by combined distillation precipitation polymerization and thiol–yne surface chemistry | |
Yu et al. | Cellulose concurrently induces predominantly one-handed helicity in helical polymers and controls the shape of optically active particles thereof | |
Rahim et al. | An overview of polymeric nano-biocomposites as targeted and controlled-release devices | |
Mukhtar et al. | Fabrication and optimization of pH-sensitive mannose-anchored nano-vehicle as a promising approach for macrophage uptake | |
Naik et al. | Development and evaluation of ibuprofen loaded hydrophilic biocompatible polymeric nanoparticles for the taste masking and solubility enhancement | |
Suntivich et al. | Gold nanoparticles grown on star-shaped block copolymer monolayers | |
Kim et al. | Molecularly smooth and conformal nanocoating by amine-mediated redox modulation of catechol | |
Ma et al. | pH-Mediated mucus penetration of zwitterionic polydopamine-modified silica nanoparticles |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: MASSACHUSETTS INSTITUTE OF TECHNOLOGY, MASSACHUSET Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GLEASON, KAREN K.;LAU, KENNETH K.S.;REEL/FRAME:018783/0166;SIGNING DATES FROM 20061204 TO 20061211 Owner name: MASSACHUSETTS INSTITUTE OF TECHNOLOGY, MASSACHUSET Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GLEASON, KAREN K.;LAU, KENNETH K.S.;SIGNING DATES FROM 20061204 TO 20061211;REEL/FRAME:018783/0166 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 4 |